CDKN1B

Summary

CDKN1B (cyclin dependent kinase inhibitor 1B, HGNC:1785) is a protein-coding gene on chromosome 12p13.1, encoding Cyclin-dependent kinase inhibitor 1B (P46527). Important regulator of cell cycle progression. In precision oncology, CDKN1B EXPRESSION confers sensitivity to Cisplatin + Fluorouracil in Head And Neck Squamous Cell Carcinoma (CIViC Level B); 1 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a cyclin-dependent kinase inhibitor, which shares a limited similarity with CDK inhibitor CDKN1A/p21. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. The degradation of this protein, which is triggered by its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes, is required for the cellular transition from quiescence to the proliferative state. Mutations in this gene are associated with multiple endocrine neoplasia type IV (MEN4).

Source: NCBI Gene 1027 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple endocrine neoplasia type 4 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 20
• Clinical variants (ClinVar): 1,122 total — 102 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 98
• Druggable target: yes
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 5 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004064

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1785
Approved symbol	CDKN1B
Name	cyclin dependent kinase inhibitor 1B
Location	12p13.1
Locus type	gene with protein product
Status	Approved
Aliases	KIP1, P27KIP1
Ensembl gene	ENSG00000111276
Ensembl biotype	protein_coding
OMIM	600778
Entrez	1027

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000228872, ENST00000396340, ENST00000442489, ENST00000477087, ENST00000614874, ENST00000682080, ENST00000682620, ENST00000683707, ENST00000684771, ENST00000907758

RefSeq mRNA: 1 — MANE Select: NM_004064 NM_004064

CCDS: CCDS8653

Canonical transcript exons

ENST00000228872 — 3 exons

Exon	Start	End
ENSE00000721808	12717368	12718314
ENSE00000993687	12721036	12722369
ENSE00003640990	12718825	12718954

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 64.7738 / max 1406.0483, expressed in 1815 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124347	56.9914	1815
124349	4.4032	961
124348	3.3792	938

Top tissues by expression

301 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	99.26	gold quality
retina	UBERON:0000966	99.23	gold quality
ventricular zone	UBERON:0003053	98.80	gold quality
ganglionic eminence	UBERON:0004023	98.60	gold quality
pons	UBERON:0000988	98.05	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.95	gold quality
trabecular bone tissue	UBERON:0002483	97.83	gold quality
parietal pleura	UBERON:0002400	97.73	gold quality
germinal epithelium of ovary	UBERON:0001304	97.69	gold quality
superficial temporal artery	UBERON:0001614	97.69	gold quality
cerebellar vermis	UBERON:0004720	97.60	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.54	gold quality
pleura	UBERON:0000977	97.50	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.48	gold quality
subthalamic nucleus	UBERON:0001906	97.47	gold quality
endothelial cell	CL:0000115	97.46	gold quality
lateral globus pallidus	UBERON:0002476	97.36	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.36	gold quality
cortical plate	UBERON:0005343	97.35	gold quality
trigeminal ganglion	UBERON:0001675	97.34	gold quality
substantia nigra pars compacta	UBERON:0001965	97.29	gold quality
olfactory bulb	UBERON:0002264	97.29	gold quality
visceral pleura	UBERON:0002401	97.28	gold quality
biceps brachii	UBERON:0001507	97.27	gold quality
bone marrow cell	CL:0002092	97.13	gold quality
eye	UBERON:0000970	96.94	gold quality
inferior vagus X ganglion	UBERON:0005363	96.94	gold quality
jejunal mucosa	UBERON:0000399	96.88	gold quality
embryo	UBERON:0000922	96.87	gold quality
adult organism	UBERON:0007023	96.84	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	32.94
E-ANND-3	yes	5.83
E-CURD-88	no	230.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AKT1, AP1, AR, ARNT, BCL6, BRCA1, CEBPE, COPS5, CTNNB1, CTNNBL1, CUX1, E2F1, E2F4, EGR2, ELF1, ELK1, EPAS1, ESR1, ESR2, ESRRG, ETS1, EWSR1, EZH2, FHL2, FLI1, FLT3, FOXA1, FOXC1, FOXM1, FOXO1, FOXO3, FOXO4, GAS6, GATA1, GATA2, GLI2, HAND1, HES1, HEY2

miRNA regulators (miRDB)

141 targeting CDKN1B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548J-3P	99.94	72.61	4881

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Rho activity can alter the translation of p27 mRNA and is important for RasV12-induced transformation in a manner dependent on p27 status (PMID:11875067)
• Inhibition of bone marrow stem cell proliferation by retinol was mediated by the up-regulation of cyclin-dependent kinase inhibitors, p21(Cip1) and p27(Kip1). (PMID:11877274)
• Retinoic acid-induced cell cycle arrest of human myeloid cell lines is associated with posttranscriptional up-regulation of p27(Kip1). (PMID:11877298)
• p27Kip1 integrates mitogenic MEK kinase- and PI3-kinase-dependent signals from TCR and CD28 to regulate cell cycle progression in primary T lymphocytes. (PMID:11884439)
• phosphorylation on serine 10 is required for its binding to CRM1 and nuclear export (PMID:11889117)
• REVIEW: gene expression regulation and role CDK inhibitor P27 in cell survival and cell cycle control in early hematopoiesis. (PMID:11908736)
• low expression may be significant and independent, unfavorable prognostic factor in renal cell carcinoma (PMID:11920465)
• Interleukin-11 induction of proliferation of human T-cells is associated with downregulation of p27(kip1). (PMID:11940481)
• Altered p27(Kip1) phosphorylation, localization, and function in human epithelial cells resistant to transforming growth factor beta-mediated G(1) arrest (PMID:11940657)
• primary hepatoblastoma well-differentiated fetal tumors without mitotic activity are strongly p27 positive (PMID:11957145)
• The COP9 signalosome inhibits p27(kip1) degradation and impedes G1-S phase progression via deneddylation of SCF Cul1. (PMID:11967155)
• High p27 levels detected in a subset of advanced breast carcinomas correlate with lymph node metastasis, suggesting that other mechanisms may bypass the cell cycle inhibitory role of p27 and provide growth advantage in these tumores. (PMID:12015771)
• Akt promotes cell-cycle progression through the mechanisms of phosphorylation-dependent 14-3-3 binding to p27(Kip1) and cytoplasmic localization. (PMID:12042314)
• The combined evaluation of p27Kip1 and Ki-67 expression provides independent information on overall survival of ovarian carcinoma patients. (PMID:12051866)
• Down-regulation of p27 is associated with malignant transformation and aggressive phenotype of cervical neoplasms. (PMID:12051885)
• Cell attachment to the extracellular matrix induces proteasomal degradation of p21(CIP1) via Cdc42/Rac1 signaling (P21CIP1) (PMID:12052868)
• P27KIP1 colocalizes with PGP9.5 in the nucleus (PMID:12082530)
• BRCA1 transactivates p27(Kip1)depending on the presence of a functional C-terminal transactivation domain. Promoter-deletion analysis identified a putative BRCA1-responsive element at position -615 to -511 of the p27(Kip1) promoter. (PMID:12082635)
• expression may be an indicator of poor prognosis in adenometroid adenocarcinoma of the uterine corpus (PMID:12085261)
• reduction in p27 accelerates gastrointestinal tumorigenesis in APC mutant mice, but not in SMAD3 mutant mice (PMID:12086850)
• p27(Kip1) is phosphorylated on serine 10 and threonine 187 by human kinase interacting stathmin, a nuclear protein that binds the C-terminal domain of p27(Kip1) and phosphorylates S10 in vitro and in vivo, promoting its nuclear export to the cytoplasm. (PMID:12093740)
• inhibits phosphorylation of retinoblastoma protein and functions as negative control in cell cycle (PMID:12101669)
• Kip1 inhibits Jab1 mediated c-Jun dependent transcription (PMID:12119282)
• P21Waf1 immunoreactivity is higher in male breast cancers compared with female breast cancers. (PMID:12123335)
• function and clinical value of cyclin E and p27 in adult acute leukemia (AL) (PMID:12133429)
• P27/Kip.1 decreased with anaplasia and was absent in glioblastomas (GBM);Skp2 was absent in well differentiated astrocytomas but was expressed in GBM. Skp2 might denote dividing cells in anaplastic gliomas or be instrumental to p27/Kip.1 degradation. (PMID:12133571)
• Androgen control of p27 stability in prostate cancer cells is mediated by F-box protein SKP2. (PMID:12188931)
• P27 is required to maintain TGF-beta mediated G1 arrest in cancer cell line. (PMID:12202478)
• exogenous p27kip1 overexpression results in cell cycle regulation in human prostate carcinoma cells; expression associated with increase in early apoptosis (PMID:12210483)
• Has prognostic value in gastric cancer (PMID:12239454)
• These data indicate that Akt may contribute to tumor-cell proliferation by phosphorylation and cytosolic retention of p27(kip1), thus relieving CDK2 from p27-induced inhibition. (PMID:12244301)
• Data show that activation of protein kinase B (PKB)/Akt, contributes to resistance to antiproliferative signals and breast cancer progression in part by impairing the nuclear import and action of p27. (PMID:12244302)
• Data show that cytoplasmic relocalization of p27(kip1), secondary to Akt-mediated phosphorylation, inactivates the growth inhibitory properties of p27(kip1) and sustains the proliferation of breast cancer cells. (PMID:12244303)
• correlates with expression of Skp2 in malignant lymphoma: correlates with proliferation index (PMID:12351407)
• This study represents the first demonstration of an increased expression of p27 in cleavage-stage human arrested embryos. (PMID:12356941)
• upregulation by Muc4/sialomucin (PMID:12386815)
• Data show that PAX3-FKHR-expressing cells had reduced expression of p27(Kip1) protein, a key cell cycle regulator. (PMID:12401804)
• The results indicate that the cell shape change caused by staurosporine correlates with the accumulation of p27kip1 and that staurosporine interferes with the p27kip1-specific proteolysis activity. (PMID:12413889)
• induction of Skp2 may be causally linked with decreased levels of p27 in prostate cancer and implicate PTEN in the regulation of Skp2 expression (PMID:12429629)
• These observations define a novel role for p27 in cell motility that is independent of its function in cell cycle inhibition. (PMID:12482975)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdkn1ba	ENSDARG00000029018
danio_rerio	cdkn1bb	ENSDARG00000054271
mus_musculus	Cdkn1b	ENSMUSG00000003031
rattus_norvegicus	Cdkn1b	ENSRNOG00000007249

Paralogs (2): CDKN1A (ENSG00000124762), CDKN1C (ENSG00000129757)

Protein

Protein identifiers

Cyclin-dependent kinase inhibitor 1B — P46527 (reviewed: P46527)

Alternative names: Cyclin-dependent kinase inhibitor p27, p27Kip1

All UniProt accessions (4): E7ES52, P46527, H7C2T1, Q6I9V6

UniProt curated annotations — full annotation on UniProt →

Function. Important regulator of cell cycle progression. Inhibits the kinase activity of CDK2 bound to cyclin A, but has little inhibitory activity on CDK2 bound to SPDYA. Involved in G1 arrest. Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. Forms a complex with cyclin type D-CDK4 complexes and is involved in the assembly, stability, and modulation of CCND1-CDK4 complex activation. Acts either as an inhibitor or an activator of cyclin type D-CDK4 complexes depending on its phosphorylation state and/or stoichometry.

Subunit / interactions. Forms a ternary complex composed of CCNE1, CDK2 and CDKN1B. Interacts directly with CCNE1; the interaction is inhibited by CDK2-dependent phosphorylation on Thr-187. Interacts with COPS5, subunit of the COP9 signalosome complex; the interaction leads to CDKN1B degradation. Interacts with NUP50; the interaction leads to nuclear import and degradation of phosphorylated CDKN1B. Interacts with CCND1 and SNX6. Interacts (Thr-198-phosphorylated form) with 14-3-3 proteins, binds strongly YWHAQ, weakly YWHAE and YWHAH, but not YWHAB nor YWHAZ; the interaction with YWHAQ results in translocation to the cytoplasm. Interacts with AKT1 and LYN; the interactions lead to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest. Forms a ternary complex with CCNA2 and CDK2; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements. Interacts (unphosphorylated form) with CDK2. Forms a complex with CDK2 and SPDYA, but does not directly interact with SPDYA. Forms a ternary complex composed of cyclin D, CDK4 and CDKN1B. Interacts (phosphorylated on Tyr-88 and Tyr-89) with CDK4; the interaction is required for cyclin D and CDK4 complex assembly, induces nuclear translocation and activates the CDK4 kinase activity. Interacts with GRB2. Interacts with PIM1. Identified in a complex with SKP1, SKP2 and CKS1B. Interacts with UHMK1; the interaction leads to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest. Also interacts with CDK1. Dephosphorylated on Thr-187 by PPM1H, leading to CDKN1B stability. Interacts with HSPA8; the interaction may be associated with susceptibility to ubiquitination.

Subcellular location. Nucleus. Cytoplasm. Endosome.

Tissue specificity. Expressed in kidney (at protein level). Expressed in all tissues tested. Highest levels in skeletal muscle, lowest in liver and kidney.

Post-translational modifications. Phosphorylated; phosphorylation occurs on serine, threonine and tyrosine residues. Phosphorylation on Ser-10 is the major site of phosphorylation in resting cells, takes place at the G(0)-G(1) phase and leads to protein stability. Phosphorylation on other sites is greatly enhanced by mitogens, growth factors, cMYC and in certain cancer cell lines. The phosphorylated form found in the cytoplasm is inactivate. Phosphorylation on Thr-198 is required for interaction with 14-3-3 proteins. Phosphorylation on Thr-187, by CDK1 and CDK2 leads to protein ubiquitination and proteasomal degradation. Tyrosine phosphorylation promotes this process. Phosphorylation by PKB/AKT1 can be suppressed by LY294002, an inhibitor of the catalytic subunit of PI3K. Phosphorylation on Tyr-88 and Tyr-89 has no effect on binding CDK2, but is required for binding CDK4. Dephosphorylated on tyrosine residues by G-CSF. Ubiquitinated; in the cytoplasm by the KPC complex (composed of RNF123/KPC1 and UBAC1/KPC2) and, in the nucleus, by SCF(SKP2). The latter requires prior phosphorylation on Thr-187. Ubiquitinated; by a TRIM21-containing SCF(SKP2)-like complex; leads to its degradation. Subject to degradation in the lysosome. Interaction with SNX6 promotes lysosomal degradation.

Disease relevance. Multiple endocrine neoplasia 4 (MEN4) [MIM:610755] Multiple endocrine neoplasia (MEN) syndromes are inherited cancer syndromes of the thyroid. MEN4 is a MEN-like syndrome with a phenotypic overlap of both MEN1 and MEN2. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. A peptide sequence containing only AA 28-79 retains substantial Kip1 cyclin A/CDK2 inhibitory activity.

Induction. Maximal levels in quiescence cells and early G(1). Levels decrease after mitogen stimulation as cells progress toward S-phase.

Miscellaneous. Decreased levels of p27Kip1, mainly due to proteasomal degradation, are found in various epithelial tumors originating from lung, breast, colon, ovary, esophagus, thyroid and prostate.

Similarity. Belongs to the CDI family.

RefSeq proteins (1): NP_004055* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003175	CDI_dom	Domain
IPR044898	CDI_dom_sf	Homologous_superfamily

Pfam: PF02234

UniProt features (42 total): mutagenesis site 13, modified residue 8, helix 4, compositionally biased region 4, region of interest 3, sequence variant 3, turn 3, chain 1, sequence conflict 1, strand 1, short sequence motif 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
7OR8	X-RAY DIFFRACTION	1.8
7ORG	X-RAY DIFFRACTION	1.8
7ORH	X-RAY DIFFRACTION	1.8
7ORS	X-RAY DIFFRACTION	1.8
6ATH	X-RAY DIFFRACTION	1.82
1H27	X-RAY DIFFRACTION	2.2
1JSU	X-RAY DIFFRACTION	2.3
2AST	X-RAY DIFFRACTION	2.3
6P8E	X-RAY DIFFRACTION	2.3
7ORT	X-RAY DIFFRACTION	2.33
6P8G	X-RAY DIFFRACTION	2.8
6P8F	X-RAY DIFFRACTION	2.89
8BYA	ELECTRON MICROSCOPY	3.38
8BYL	ELECTRON MICROSCOPY	3.5
8BZO	ELECTRON MICROSCOPY	3.5
5UQ3	X-RAY DIFFRACTION	3.6
7B5L	ELECTRON MICROSCOPY	3.8
7B5R	ELECTRON MICROSCOPY	3.8
7B5M	ELECTRON MICROSCOPY	3.91

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46527-F1	71.08	0.36

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (8): 74, 88, 89, 157, 170, 187, 198, 10

Mutagenesis-validated functional residues (13):

Position	Phenotype
10	loss of phosphorylation by uhmk1. no translocation to the cytoplasm. greater cell cycle arrest.
10	exported to the cytoplasm. inhibits cell cycle arrest.
10	increased stability in vivo and in vitro.
74	no change in binding cdk4 and no inhibition of cdk4 activity. translocates to nucleus. no effect on in vitro phosphoryla
88	abolishes lyn-mediated phosphorylation, reduces cdk2-mediated phosphorylation on t-187, has greater cell cycle arrest in
89	no effect on binding cdk2 complexes, reduced cdk4 binding and greatly inhibits cdk4 enzyme activity. no nuclear transloc
157	greatly reduced pkb/akt1-mediated phosphorylation. nuclear location. inhibits cyclin e/cdk2 cell cycle progression. no e
161	no change in pkb/akt1-mediated phosphorylation.
162	no change in pkb/akt1-mediated phosphorylation.
185	strongly reduced ubiquitination by a trim21-containing scf(skp2) complex.
187	no change in pkb/akt1- nor uhmk1-mediated phosphorylation.
187	abolishes phosphorylation-dependent ubiquitination.
198	abolishes pkb/akt1-mediated phosphorylation. 46% cytoplasmic location. greatly reduced binding to ywhaq. equally reduced

Function

Pathways and Gene Ontology

Reactome pathways

53 pathways

ID	Pathway
R-HSA-187577	SCF(Skp2)-mediated degradation of p27/p21
R-HSA-198323	AKT phosphorylates targets in the cytosol
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-5625900	RHO GTPases activate CIT
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-6804116	TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest
R-HSA-69202	Cyclin E associated events during G1/S transition
R-HSA-69231	Cyclin D associated events in G1
R-HSA-69563	p53-Dependent G1 DNA Damage Response
R-HSA-69656	Cyclin A:Cdk2-associated events at S phase entry
R-HSA-8849470	PTK6 Regulates Cell Cycle
R-HSA-9607240	FLT3 Signaling
R-HSA-9617828	FOXO-mediated transcription of cell cycle genes
R-HSA-9634638	Estrogen-dependent nuclear events downstream of ESR-membrane signaling
R-HSA-9661069	Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-168256	Immune System
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-212436	Generic Transcription Pathway
R-HSA-2219528	PI3K/AKT Signaling in Cancer
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-453279	Mitotic G1 phase and G1/S transition

MSigDB gene sets: 803 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, BIOCARTA_PTEN_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, ACTACCT_MIR196A_MIR196B, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, PID_TELOMERASE_PATHWAY, HARRIS_HYPOXIA, GOBP_REGULATION_OF_PHOSPHORYLATION

GO Biological Process (43): regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0000079), G1/S transition of mitotic cell cycle (GO:0000082), placenta development (GO:0001890), potassium ion transport (GO:0006813), regulation of exit from mitosis (GO:0007096), Notch signaling pathway (GO:0007219), heart development (GO:0007507), sensory perception of sound (GO:0007605), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), negative regulation of cell growth (GO:0030308), DNA damage response, signal transduction by p53 class mediator (GO:0030330), regulation of cell migration (GO:0030334), positive regulation of microtubule polymerization (GO:0031116), positive regulation of protein catabolic process (GO:0045732), positive regulation of DNA replication (GO:0045740), negative regulation of mitotic cell cycle (GO:0045930), autophagic cell death (GO:0048102), inner ear development (GO:0048839), negative regulation of epithelial cell proliferation (GO:0050680), nuclear export (GO:0051168), regulation of cell cycle (GO:0051726), epithelial cell proliferation involved in prostate gland development (GO:0060767), negative regulation of epithelial cell proliferation involved in prostate gland development (GO:0060770), cellular response to antibiotic (GO:0071236), cellular response to lithium ion (GO:0071285), cellular senescence (GO:0090398), regulation of lens fiber cell differentiation (GO:1902746), regulation of cell cycle G1/S phase transition (GO:1902806), epithelial cell apoptotic process (GO:1904019), negative regulation of epithelial cell apoptotic process (GO:1904036), negative regulation of vascular associated smooth muscle cell proliferation (GO:1904706), negative regulation of cardiac muscle tissue regeneration (GO:1905179), regulation of G1/S transition of mitotic cell cycle (GO:2000045), apoptotic process (GO:0006915), regulation of mitotic cell cycle (GO:0007346), programmed cell death (GO:0012501), negative regulation of kinase activity (GO:0033673), negative regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0045736), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (13): protein kinase inhibitor activity (GO:0004860), cyclin-dependent protein serine/threonine kinase inhibitor activity (GO:0004861), protein kinase binding (GO:0019901), protein phosphatase binding (GO:0019903), cyclin-dependent protein kinase regulator activity (GO:0019914), cyclin binding (GO:0030332), ubiquitin protein ligase binding (GO:0031625), protein-containing complex binding (GO:0044877), protein-folding chaperone binding (GO:0051087), molecular adaptor activity (GO:0060090), molecular function inhibitor activity (GO:0140678), ubiquitin ligase activator activity (GO:1990757), protein binding (GO:0005515)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endosome (GO:0005768), centrosome (GO:0005813), cytosol (GO:0005829), cilium (GO:0005929), Cul4A-RING E3 ubiquitin ligase complex (GO:0031464), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
Cellular Senescence	2
Cyclin E associated events during G1/S transition	1
Cyclin A:Cdk2-associated events at S phase entry	1
PIP3 activates AKT signaling	1
RHO GTPase Effectors	1
PI3K/AKT Signaling in Cancer	1
TP53 Regulates Transcription of Cell Cycle Genes	1
G1/S Transition	1
G1 Phase	1
p53-Dependent G1/S DNA damage checkpoint	1
S Phase	1
Signaling by PTK6	1
Cytokine Signaling in Immune system	1
FOXO-mediated transcription	1
Extra-nuclear estrogen signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	3
cyclin-dependent protein serine/threonine kinase activity	2
mitotic cell cycle	2
animal organ development	2
cell population proliferation	2
regulation of cell population proliferation	2
negative regulation of cellular process	2
protein kinase regulator activity	2
protein binding	2
microtubule organizing center	2
cilium	2
regulation of protein serine/threonine kinase activity	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
metal ion transport	1
exit from mitosis	1
regulation of mitotic cell cycle phase transition	1
cell surface receptor signaling pathway	1
circulatory system development	1
sensory perception of mechanical stimulus	1
positive regulation of cellular process	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
cell migration	1
regulation of cell motility	1
positive regulation of microtubule polymerization or depolymerization	1
regulation of microtubule polymerization	1
positive regulation of protein polymerization	1
microtubule polymerization	1
positive regulation of supramolecular fiber organization	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
DNA replication	1
regulation of DNA replication	1

Protein interactions and networks

STRING

3848 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDKN1B	CDK2	P24941	999
CDKN1B	CCNA2	P20248	997
CDKN1B	CCNA1	P78396	997
CDKN1B	CDK4	P11802	996
CDKN1B	CCNL2	Q96S94	995
CDKN1B	CCND1	P24385	992
CDKN1B	CDK6	Q00534	984
CDKN1B	SKP2	Q13309	948
CDKN1B	COPS5	Q92905	937
CDKN1B	CDKN2C	P42773	915
CDKN1B	TP53	P04637	911
CDKN1B	RHOA	P06749	910
CDKN1B	CCND3	P30281	902
CDKN1B	STMN1	P16949	899
CDKN1B	FOXO3	O43524	869

IntAct

255 interactions, top by confidence:

A	B	Type	Score
CDK4	CCND1	psi-mi:“MI:0914”(association)	0.990
CCND1	CDK4	psi-mi:“MI:0914”(association)	0.990
CCNA2	CDK2	psi-mi:“MI:0915”(physical association)	0.980
CCNA2	CDK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.980
CCND3	CDK4	psi-mi:“MI:0914”(association)	0.980
CDK2	CCNE1	psi-mi:“MI:0914”(association)	0.970
CCNE1	CDK2	psi-mi:“MI:0914”(association)	0.970
CDKN1B	CCNA2	psi-mi:“MI:0915”(physical association)	0.970
CDK2	CDKN1B	psi-mi:“MI:0407”(direct interaction)	0.970
CCNA2	CDKN1B	psi-mi:“MI:0407”(direct interaction)	0.970
CCNA2	CDKN1B	psi-mi:“MI:0915”(physical association)	0.970
CDKN1B	CDK2	psi-mi:“MI:0407”(direct interaction)	0.970
CDKN1B	CCNA2	psi-mi:“MI:0407”(direct interaction)	0.970
CDKN1B	CDK2	psi-mi:“MI:0915”(physical association)	0.970
CDK2	CDKN1B	psi-mi:“MI:0915”(physical association)	0.970
CDK2	CDKN1B	psi-mi:“MI:0914”(association)	0.970

BioGRID (532): CDKN1B (Biochemical Activity), CDKN1B (Biochemical Activity), CDKN1B (Two-hybrid), COPS5 (Affinity Capture-Western), CDKN1B (Affinity Capture-Western), TXNIP (Affinity Capture-Western), CDKN1B (Affinity Capture-Western), COPS5 (Affinity Capture-Western), CDKN1B (Reconstituted Complex), CDKN1B (Biochemical Activity), CDKN1B (Reconstituted Complex), CDKN1B (Biochemical Activity), CDKN1B (Reconstituted Complex), CDKN1B (Biochemical Activity), CDKN1B (Biochemical Activity)

ESM2 similar proteins: A0A1L8GUX5, A2AHC3, A2AIW0, A2CE83, A5D8S8, A5WUN7, E2QSX5, F1R983, O94992, P28290, P46414, P46527, P46529, P61406, Q08DX0, Q0X0C4, Q13009, Q13111, Q28GJ0, Q2KJD6, Q3UHU5, Q4V7W3, Q502L1, Q503Y8, Q5M9G1, Q5RAK6, Q5SXA9, Q5T5Y3, Q5U3H9, Q60439, Q60610, Q60664, Q62627, Q640U0, Q641E3, Q6NXJ0, Q6PCQ0, Q6RFY2, Q6WCQ1, Q6ZMN7

Diamond homologs: O19001, O19002, P38936, P39689, P46414, P46527, P46529, P49918, P49919, Q60439, Q6SLL5

SIGNOR signaling

87 interactions.

A	Effect	B	Mechanism
CUL1	“down-regulates quantity by destabilization”	CDKN1B	ubiquitination
MYC	“down-regulates quantity by repression”	CDKN1B	“transcriptional regulation”
YWHAH	down-regulates	CDKN1B	binding
AKT1	down-regulates	CDKN1B	phosphorylation
CDKN1B	down-regulates	CDK1	binding
SKP2	down-regulates	CDKN1B	ubiquitination
CDK6	up-regulates	CDKN1B	phosphorylation
CDK6	down-regulates	CDKN1B	phosphorylation
BRCA1	“up-regulates quantity by expression”	CDKN1B	“transcriptional regulation”
FOXA1	“up-regulates quantity by expression”	CDKN1B	“transcriptional regulation”
SRC	down-regulates	CDKN1B	phosphorylation
TGFB1	“up-regulates quantity by expression”	CDKN1B
CDK2	down-regulates	CDKN1B	phosphorylation
CDKN1B	down-regulates	CDK2	binding
LYN	down-regulates	CDKN1B	phosphorylation
HIPK2	up-regulates	CDKN1B	phosphorylation
AKT1	“down-regulates quantity by repression”	CDKN1B	“transcriptional regulation”
CDKN1B	up-regulates	Cell_cycle_block
SGK1	down-regulates	CDKN1B	phosphorylation
SGK1	“down-regulates activity”	CDKN1B	phosphorylation
PIM1	down-regulates	CDKN1B	phosphorylation
PIM1	“down-regulates activity”	CDKN1B	phosphorylation
AKT	down-regulates	CDKN1B	binding
SCF-betaTRCP	down-regulates	CDKN1B	ubiquitination
CDKN1B	“down-regulates activity”	CyclinE/CDK2	binding
CDKN1B	down-regulates	Cell_cycle_progress

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	8	83.2×	1e-12
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	77.1×	8e-11
TP53 Regulates Transcription of Cell Cycle Genes	8	71.3×	5e-12
G1 Phase	11	71.0×	3e-16
TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest	5	58.5×	3e-07
p53-Dependent G1 DNA Damage Response	5	58.5×	3e-07
p53-Dependent G1/S DNA damage checkpoint	5	58.5×	3e-07
G1/S DNA Damage Checkpoints	5	55.1×	4e-07

GO biological processes:

GO term	Partners	Fold	FDR
G1/S transition of mitotic cell cycle	17	44.9×	4e-21
positive regulation of G1/S transition of mitotic cell cycle	5	26.4×	2e-04
G2/M transition of mitotic cell cycle	6	24.6×	3e-05
regulation of mitotic cell cycle	7	22.2×	6e-06
positive regulation of fibroblast proliferation	5	19.4×	8e-04
cell division	22	13.4×	2e-16
protein-containing complex assembly	6	9.0×	4e-03
regulation of cell cycle	7	6.9×	4e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 5 cancer types — BRCA, HCC, PCM, PRAD, SIC.

Clinical variants and AI predictions

ClinVar

1122 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	102
Likely pathogenic	13
Uncertain significance	601
Likely benign	248
Benign	20

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068845	NM_004064.5(CDKN1B):c.186del (p.Phe62fs)	Pathogenic
1069229	NM_004064.5(CDKN1B):c.276del (p.Arg93fs)	Pathogenic
1069331	NM_004064.5(CDKN1B):c.80_81del (p.Ser27fs)	Pathogenic
1070862	NC_000012.11:g.(?12870768)(12871886_?)del	Pathogenic
1072624	NM_004064.5(CDKN1B):c.385dup (p.His129fs)	Pathogenic
1072930	NM_004064.5(CDKN1B):c.15_16dup (p.Val6fs)	Pathogenic
1075662	NM_004064.5(CDKN1B):c.174del (p.Lys59fs)	Pathogenic
1386042	NM_004064.5(CDKN1B):c.267_268del (p.Tyr89_Arg90delinsTer)	Pathogenic
1398606	NM_004064.5(CDKN1B):c.460C>T (p.Arg154Ter)	Pathogenic
1405782	NM_004064.5(CDKN1B):c.226_227insA (p.Trp76Ter)	Pathogenic
1410246	NM_004064.5(CDKN1B):c.86dup (p.Cys29fs)	Pathogenic
1413501	NM_004064.5(CDKN1B):c.388_392del (p.Leu130fs)	Pathogenic
1439402	NM_004064.5(CDKN1B):c.421C>T (p.Gln141Ter)	Pathogenic
1452550	NM_004064.5(CDKN1B):c.487C>T (p.Gln163Ter)	Pathogenic
1453444	NM_004064.5(CDKN1B):c.185dup (p.Asp63fs)	Pathogenic
1455877	NM_004064.5(CDKN1B):c.410del (p.Pro137fs)	Pathogenic
157519	NM_004064.5(CDKN1B):c.279_280insT (p.Pro94fs)	Pathogenic
1728762	NM_004064.5(CDKN1B):c.319C>T (p.Gln107Ter)	Pathogenic
1729610	NM_004064.5(CDKN1B):c.326del (p.Val109fs)	Pathogenic
1769065	NM_004064.5(CDKN1B):c.128delinsCA (p.Arg43fs)	Pathogenic
1780338	NM_004064.5(CDKN1B):c.179G>A (p.Trp60Ter)	Pathogenic
1780560	NM_004064.5(CDKN1B):c.180G>A (p.Trp60Ter)	Pathogenic
1784392	NM_004064.5(CDKN1B):c.201_202del (p.His67fs)	Pathogenic
183391	NM_004064.5(CDKN1B):c.59_77dup (p.Ser27fs)	Pathogenic
183395	NM_004064.5(CDKN1B):c.374_375del (p.Asn124_Ser125insTer)	Pathogenic
2018951	NM_004064.5(CDKN1B):c.413_414dup (p.Asp139fs)	Pathogenic
2092093	NM_004064.5(CDKN1B):c.396_397insTT (p.Pro133fs)	Pathogenic
2419784	NM_004064.5(CDKN1B):c.375dup (p.Glu126Ter)	Pathogenic
2450777	NM_004064.5(CDKN1B):c.369dup (p.Asn124Ter)	Pathogenic
2450781	NM_004064.5(CDKN1B):c.389del (p.Leu130fs)	Pathogenic

SpliceAI

943 predictions. Top by Δscore:

Variant	Effect	Δscore
12:12718288:GAA:G	donor_gain	1.0000
12:12718295:G:GT	donor_gain	1.0000
12:12718950:GCTCG:G	donor_gain	1.0000
12:12719647:G:GG	donor_gain	1.0000
12:12687021:A:AC	donor_gain	0.9900
12:12687022:C:CC	donor_gain	0.9900
12:12687024:TTTG:T	donor_gain	0.9900
12:12696064:CGAG:C	donor_gain	0.9900
12:12718311:GACG:G	donor_gain	0.9900
12:12718313:CGGTA:C	donor_loss	0.9900
12:12718314:GGT:G	donor_loss	0.9900
12:12718315:G:GG	donor_gain	0.9900
12:12718315:GTA:G	donor_loss	0.9900
12:12718316:T:A	donor_loss	0.9900
12:12718804:A:AG	acceptor_gain	0.9900
12:12718805:A:G	acceptor_gain	0.9900
12:12718807:A:G	acceptor_gain	0.9900
12:12718823:A:AG	acceptor_gain	0.9900
12:12718824:G:GG	acceptor_gain	0.9900
12:12718951:C:G	donor_gain	0.9900
12:12719034:C:T	donor_gain	0.9900
12:12721035:GA:G	acceptor_gain	0.9900
12:12696063:A:AC	donor_gain	0.9800
12:12696064:C:CC	donor_gain	0.9800
12:12696147:C:CA	donor_gain	0.9800
12:12696148:C:A	donor_gain	0.9800
12:12718816:T:A	acceptor_gain	0.9800
12:12718818:C:CA	acceptor_gain	0.9800
12:12718937:TCAA:T	donor_gain	0.9800
12:12718943:G:GG	donor_gain	0.9800

AlphaMissense

1302 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:12717936:T:C	F33L	1.000
12:12717938:C:A	F33L	1.000
12:12717938:C:G	F33L	1.000
12:12718065:T:A	W76R	1.000
12:12718065:T:C	W76R	1.000
12:12718067:G:C	W76C	1.000
12:12718067:G:T	W76C	1.000
12:12717928:G:C	R30T	0.999
12:12717928:G:T	R30M	0.999
12:12717929:G:C	R30S	0.999
12:12717929:G:T	R30S	0.999
12:12717936:T:A	F33I	0.999
12:12717936:T:G	F33V	0.999
12:12717937:T:C	F33S	0.999
12:12718017:T:A	W60R	0.999
12:12718017:T:C	W60R	0.999
12:12718023:T:C	F62L	0.999
12:12718024:T:C	F62S	0.999
12:12718025:C:A	F62L	0.999
12:12718025:C:G	F62L	0.999
12:12718066:G:C	W76S	0.999
12:12717934:T:A	L32H	0.998
12:12717934:T:C	L32P	0.998
12:12717937:T:G	F33C	0.998
12:12717940:G:A	G34D	0.998
12:12718018:G:C	W60S	0.998
12:12718019:G:C	W60C	0.998
12:12718019:G:T	W60C	0.998
12:12718030:T:C	F64S	0.998
12:12718029:T:C	F64L	0.997

dbSNP variants (sampled 300 via entrez): RS1001410752 (12:12715945 T>C), RS1001429930 (12:12717136 G>A), RS1001508784 (12:12720859 G>A), RS1001663523 (12:12722040 A>G), RS1001986580 (12:12722302 T>C), RS1002106899 (12:12719509 T>A,G), RS1002176228 (12:12718412 G>A), RS1002395512 (12:12720543 C>G,T), RS1002565992 (12:12719182 G>T), RS1002778305 (12:12717569 C>T), RS1003011893 (12:12715575 C>A), RS1003069255 (12:12716234 G>A), RS1003100512 (12:12715880 T>C), RS1003239437 (12:12717423 C>A,T), RS1003665057 (12:12719067 A>G)

Disease associations

OMIM: gene MIM:600778 | disease phenotypes: MIM:610755, MIM:131100, MIM:120435, MIM:167000, MIM:114500

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple endocrine neoplasia type 4	Definitive	Autosomal dominant
multiple endocrine neoplasia	Strong	Autosomal dominant
hereditary nonpolyposis colon cancer	Limited	Unknown

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
multiple endocrine neoplasia type 4	Definitive	AD
hereditary nonpolyposis colon cancer	Limited	AR

Mondo (9): multiple endocrine neoplasia type 4 (MONDO:0012552), hereditary neoplastic syndrome (MONDO:0015356), neuroendocrine neoplasm (MONDO:0019496), primary hyperparathyroidism (MONDO:0010837), multiple endocrine neoplasia type 1 (MONDO:0007540), hereditary nonpolyposis colon cancer (MONDO:0018630), ovarian cancer (MONDO:0008170), colorectal cancer (MONDO:0005575), multiple endocrine neoplasia (MONDO:0017169)

Orphanet (7): Inherited cancer-predisposing syndrome (Orphanet:140162), Multiple endocrine neoplasia type 4 (Orphanet:276152), Neuroendocrine neoplasm (Orphanet:877), Multiple endocrine neoplasia type 1 (Orphanet:652), Hereditary nonpolyposis colon cancer (Orphanet:443909), Rare ovarian cancer (Orphanet:213500), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

98 total (30 of 98 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000141	Amenorrhea
HP:0000169	Gingival fibromatosis
HP:0000716	Depression
HP:0000736	Short attention span
HP:0000787	Nephrolithiasis
HP:0000802	Impotence
HP:0000818	Abnormality of the endocrine system
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0000825	Hyperinsulinemic hypoglycemia
HP:0000843	Hyperparathyroidism
HP:0000845	Elevated circulating growth hormone concentration
HP:0000849	Adrenocortical abnormality
HP:0000853	Goiter
HP:0000854	Thyroid adenoma
HP:0000872	Hashimoto thyroiditis
HP:0001012	Multiple lipomas
HP:0001031	Subcutaneous lipoma
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001289	Confusion
HP:0001293	Cranial nerve compression
HP:0001579	Primary hypercortisolism
HP:0001824	Weight loss
HP:0001944	Dehydration
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002018	Nausea
HP:0002019	Constipation

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST001795_7	Systemic lupus erythematosus	5.000000e-12
GCST006010_15	Mean arterial pressure	3.000000e-08
GCST006085_54	Prostate cancer	2.000000e-09
GCST007703_80	Systolic blood pressure	7.000000e-07
GCST007704_54	Diastolic blood pressure	9.000000e-07
GCST007706_109	Mean arterial pressure	1.000000e-07
GCST008860_2	Prostate cancer	6.000000e-12
GCST009066_48	Mosaic loss of chromosome Y (Y chromosome dosage)	2.000000e-10
GCST009379_334	Type 2 diabetes	4.000000e-08
GCST009391_366	Metabolite levels	4.000000e-06
GCST009391_954	Metabolite levels	5.000000e-06
GCST010002_209	Refractive error	4.000000e-34
GCST010703_173	Brain morphology (MOSTest)	4.000000e-11
GCST011956_133	Systemic lupus erythematosus	1.000000e-43
GCST90000025_1022	Appendicular lean mass	2.000000e-16
GCST90000025_1023	Appendicular lean mass	2.000000e-33
GCST90000026_36	Appendicular lean mass	3.000000e-11
GCST90000027_16	Appendicular lean mass	3.000000e-07
GCST90002394_364	Monocyte percentage of white cells	3.000000e-11
GCST90002400_76	Plateletcrit	5.000000e-22

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0006340	mean arterial pressure
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0007783	mosaic loss of chromosome Y measurement
EFO:0010435	triacylglycerol 56:8 measurement
EFO:0010443	triacylglycerol 58:9 measurement
EFO:0004346	neuroimaging measurement
EFO:0004980	appendicular lean mass
EFO:0007989	monocyte percentage of leukocytes
EFO:0007985	platelet crit

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D049950	Hyperparathyroidism, Primary	C19.642.355.239
D009377	Multiple Endocrine Neoplasia	C04.588.322.400; C04.651.600; C04.700.630; C16.320.700.630; C19.344.400
D018761	Multiple Endocrine Neoplasia Type 1	C04.588.322.400.500; C04.651.600.500; C04.700.630.500; C16.320.700.630.500; C19.344.400.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D018358	Neuroendocrine Tumors	C04.557.465.625.650; C04.557.580.625.650
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
C567059	Multiple Endocrine Neoplasia, Type IV (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3758070 (SINGLE PROTEIN), CHEMBL3885557 (PROTEIN-PROTEIN INTERACTION)

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
CDKN1B EXPRESSION	Cisplatin + Fluorouracil	Head And Neck Squamous Cell Carcinoma	Sensitivity/Response	CIViC B	EID889
CDKN1B CYTOPLASMIC MISLOCALIZATION	Lapatinib	Breast Cancer	Resistance	CIViC D	EID860

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

358 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects reaction, increases expression, affects cotreatment, decreases reaction, affects binding (+1 more)	18
Tretinoin	increases reaction, increases phosphorylation, increases expression, affects expression, affects cotreatment (+8 more)	15
Arsenic Trioxide	affects cotreatment, increases expression, decreases expression, increases localization, increases reaction	14
Troglitazone	affects cotreatment, decreases expression, affects binding, increases expression, increases reaction (+4 more)	12
sodium arsenite	decreases expression, affects expression, affects binding, decreases reaction, affects cotreatment (+3 more)	9
(+)-JQ1 compound	affects cotreatment, increases expression, decreases expression	9
Bortezomib	affects cotreatment, increases cleavage, increases expression, increases reaction, increases stability	9
Calcitriol	increases reaction, decreases degradation, decreases phosphorylation, increases stability, affects cotreatment (+2 more)	8
Cisplatin	affects expression, affects reaction, increases expression, decreases response to substance, increases phosphorylation (+3 more)	8
Vorinostat	affects cotreatment, increases cleavage, increases expression, increases reaction	7
Curcumin	affects reaction, increases expression, decreases expression, decreases reaction, increases reaction (+1 more)	7
Sirolimus	affects cotreatment, affects localization, affects binding, decreases reaction, increases phosphorylation (+3 more)	7
bisphenol A	affects expression, affects cotreatment, decreases methylation, decreases expression, increases expression (+1 more)	6
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases reaction, affects cotreatment, affects expression, increases response to substance	6
Doxorubicin	decreases response to substance, affects expression, affects cotreatment, increases expression, increases reaction	6
Estradiol	decreases reaction, increases degradation, increases expression, increases reaction, affects reaction (+4 more)	6
Cadmium Chloride	decreases expression, decreases phosphorylation, increases abundance, increases expression, increases reaction (+1 more)	6
Gefitinib	affects cotreatment, increases expression, decreases expression, increases reaction	5
Fulvestrant	affects cotreatment, decreases methylation, increases expression, decreases reaction, increases degradation	5
Quercetin	affects cotreatment, affects reaction, increases expression, decreases reaction, affects binding (+1 more)	5
Valproic Acid	increases expression, increases reaction, affects expression, affects cotreatment, decreases expression	5
trichostatin A	increases reaction, affects expression, affects cotreatment, increases expression	4
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases expression, affects cotreatment	4
Indomethacin	increases expression, affects cotreatment, decreases expression	4
Mifepristone	affects cotreatment, affects binding, increases reaction, decreases activity, increases expression (+3 more)	4
Simvastatin	decreases activity, decreases degradation, increases expression	4
indole-3-carbinol	increases expression	3
lactacystin	decreases reaction, increases degradation, increases expression	3
alvocidib	increases cleavage, increases expression	3
U 0126	increases reaction, affects cotreatment, decreases reaction, increases expression	3

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4131150	Binding	Activation of human P27kip1 at 0.40 uM using TMB as substrate by ELISA (Rvb = 0%)	Novel pyrazolopyrimidines: Synthesis, in vitro cytotoxic activity and mechanistic investigation. — Eur J Med Chem

Cellosaurus cell lines

14 cell lines: 11 cancer cell line, 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1997	COLO 783	Cancer cell line	Female
CVCL_A0M5	SEES3-1V human CDKN1B, clone1	Embryonic stem cell	Male
CVCL_A0M6	SEES3-1V human CDKN1B, clone2	Embryonic stem cell	Male
CVCL_A0M7	SEES3-1V human CDKN1B, clone3	Embryonic stem cell	Male
CVCL_B8DH	Abcam HCT 116 CDKN1B KO	Cancer cell line	Male
CVCL_B8U0	Abcam MCF-7 CDKN1B KO	Cancer cell line	Female
CVCL_B9FQ	Abcam A-549 CDKN1B KO	Cancer cell line	Male
CVCL_C1ME	ALL-VG	Cancer cell line	Male
CVCL_C1MF	ALL-VG TKI-resistant	Cancer cell line	Male
CVCL_D7ME	Ubigene A-549 CDKN1B KO	Cancer cell line	Male

Clinical trials (associated diseases)

363 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00204373	PHASE4	COMPLETED	Treatment of Zollinger-Ellison Syndrome With Prevacid
NCT01317615	PHASE4	COMPLETED	RAD001 With Paclitaxel and Carboplatin in First Line Treatment of Patients With Advanced Large Cell Lung Cancer With Neuroendocrine Differentiation
NCT01595009	PHASE4	COMPLETED	An Open-label, Multi-center, Expanded Access Study of Everolimus in Participants With Advanced Neuroendocrine Tumors (NETs) (Core Study) and an Extension Study to the Open-label, Multi-center, Expanded Access Study of Everolimus in Patients With Advanced NETs (E1)
NCT01794793	PHASE4	COMPLETED	Study to Allow Access to Pasireotide for Patients Benefiting From Pasireotide Treatment in Novartis-sponsored Studies
NCT02075606	PHASE4	COMPLETED	Circulating Tumour Cells in Somatuline Autogel Treated NeuroEndocrine Tumours Patients
NCT03083210	PHASE4	UNKNOWN	Study of Lanreotide in Metastatic or Recurrent Grade I-II Hindgut NET
NCT03289741	PHASE4	COMPLETED	A Study to Evaluate Patient Experience in the Therapy of Neuroendocrine Tumors Treated With Octreotide Long Acting Release Versus Lanreotide
NCT04140409	PHASE4	TERMINATED	Sandostatin (Octreotide LAR) May Lead to Clinical Improvement Through Receptor Occupation Optimisation
NCT06485739	PHASE4	NOT_YET_RECRUITING	Irinotecan Liposomes for the Treatment of Neuroendocrine Carcinoma
NCT07272512	PHASE4	RECRUITING	Prospective Multicenter Real-world Study of Surufatinib in Patients With Advanced Neuroendocrine Neoplasms
NCT00037869	PHASE3	COMPLETED	High Dose I-131 Metaiodobenzylguanidine(MIBG) for Metastatic Neuroendocrine Tumors
NCT00171873	PHASE3	COMPLETED	Antiproliferative Effect of Octreotide in Patients With Metastasized Neuroendocrine Tumors of the Midgut
NCT00227136	PHASE3	TERMINATED	Effect of Oral 5-HTP Intake on Urinary 5-HIAA Excretion
NCT00569127	PHASE3	ACTIVE_NOT_RECRUITING	Octreotide Acetate and Recombinant Interferon Alfa-2b or Bevacizumab in Treating Patients With Metastatic or Locally Advanced, High-Risk Neuroendocrine Tumor
NCT01524783	PHASE3	COMPLETED	Everolimus Plus Best Supportive Care vs Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Neuroendocrine Tumors (GI or Lung Origin)
NCT01578239	PHASE3	COMPLETED	A Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours
NCT01755182	PHASE3	TERMINATED	Systemic Therapy With or Without Upfront Transarterial Embolization for Inoperable Liver Metastasis of Neuroendocrine Tumors
NCT02246127	PHASE3	COMPLETED	Sequentiality of Everolimus and STZ-5FU in Advanced Pancreatic Neuroendocrine Tumor
NCT02588170	PHASE3	COMPLETED	Phase III Study of Surufatinib in Treating Advanced Extrapancreatic Neuroendocrine Tumors
NCT02589821	PHASE3	COMPLETED	Phase III Study of Surufatinib in Treating Advanced Pancreatic Neuroendocrine Tumors
NCT02840149	PHASE3	COMPLETED	SUV on 68Ga-DOTATATE PET/CT and Ki-67 Index in Neuro-Endocrine Tumors
NCT03042416	PHASE3	COMPLETED	18F-DOPA PET Imaging: an Evaluation of Biodistribution and Safety
NCT03049189	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of 177Lu-edotreotide PRRT in GEP-NET Patients
NCT03136328	PHASE3	COMPLETED	Diagnosis and Staging of Neuroendocrine Tumors (NETs) Utilizing 68Ga-DOTATOC PET/CT Scan
NCT03375320	PHASE3	ACTIVE_NOT_RECRUITING	Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors
NCT03673943	PHASE3	COMPLETED	Imaging of Patients With Known or Suspected Somatostatin Receptor Positive Neuroendocrine Tumors Using Cu64-DOTATATE
NCT04706910	PHASE3	RECRUITING	18F-DOPA II - PET Imaging Optimization
NCT04810091	PHASE3	ACTIVE_NOT_RECRUITING	Telotristat Ethyl for the Treatment of Carcinoid Heart Disease in Patients With Metastatic Neuroendocrine Tumor
NCT04847505	PHASE3	RECRUITING	68Ga-DOTA-TATE PET/CT Imaging in NETs
NCT04919226	PHASE3	ACTIVE_NOT_RECRUITING	Lutetium 177Lu-Edotreotide Versus Best Standard of Care in Well-differentiated Aggressive Grade-2 and Grade-3 GastroEnteroPancreatic NeuroEndocrine Tumors (GEP-NETs) - COMPOSE
NCT05387603	PHASE3	RECRUITING	Systemic Targeted Adaptive RadioTherapy of NeuroEndocrine Tumors.
NCT05459844	PHASE3	ACTIVE_NOT_RECRUITING	A Study Comparing Treatment With Lutetium[177Lu] Oxodotreotide Injection to Octreotide LAR in Patients With GEP-NETs
NCT05477576	PHASE3	RECRUITING	Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy
NCT05918302	PHASE3	RECRUITING	Efficacy and Safety of Radiotherapy Compared to Everolimus in Somatostatin Receptor Positive Neuroendocrine Tumors of the Lung and Thymus.
NCT06240741	PHASE3	COMPLETED	A Prospective, Open-label Study of [68Ga]Ga-DOTA-TATE in Patients With Neuroendocrine Neoplasms (NENs) and Healthy Volunteers in Japan
NCT00001277	PHASE2	COMPLETED	Studies of Elevated Parathyroid Activity
NCT00947167	PHASE2	TERMINATED	A Phase II Study of Pertuzumab and Erlotinib for Metastatic or Unresectable Neuroendocrine Tumors
NCT00990535	PHASE2	COMPLETED	High Dose Somatostatin Analogues in Neuroendocrine Tumors
NCT03452111	PHASE2	COMPLETED	Study of Daily Application of Nestorone® (NES) and Testosterone (T) Combination Gel for Male Contraception
NCT03455075	PHASE2	COMPLETED	Study of Spermatogenesis Suppression With DMAU Alone or With LNG Versus Placebo Alone in Normal Men