CDKN1A

Summary

CDKN1A (cyclin dependent kinase inhibitor 1A, HGNC:1784) is a protein-coding gene on chromosome 6p21.2, encoding Cyclin-dependent kinase inhibitor 1 (P38936). Plays an important role in controlling cell cycle progression and DNA damage-induced G2 arrest. In precision oncology, CDKN1A EXPRESSION is associated with resistance to Fluorouracil in Colorectal Cancer (CIViC Level B).

This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-cyclin-dependent kinase2 or -cyclin-dependent kinase4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This protein can interact with proliferating cell nuclear antigen, a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of cyclin-dependent kinase2, and may be instrumental in the execution of apoptosis following caspase activation. Mice that lack this gene have the ability to regenerate damaged or missing tissue. Multiple alternatively spliced variants have been found for this gene.

Source: NCBI Gene 1026 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 47 total — 1 pathogenic
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 3 cancer types
• MANE Select transcript: NM_000389

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1784
Approved symbol	CDKN1A
Name	cyclin dependent kinase inhibitor 1A
Location	6p21.2
Locus type	gene with protein product
Status	Approved
Aliases	P21, CIP1, WAF1, SDI1, CAP20, p21CIP1, p21Cip1/Waf1, p21
Ensembl gene	ENSG00000124762
Ensembl biotype	protein_coding
OMIM	116899
Entrez	1026

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 36 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000244741, ENST00000373711, ENST00000405375, ENST00000448526, ENST00000459970, ENST00000462537, ENST00000478800, ENST00000615513, ENST00000864199, ENST00000864200, ENST00000864201, ENST00000864202, ENST00000864203, ENST00000864204, ENST00000864205, ENST00000864206, ENST00000864207, ENST00000911804, ENST00000911805, ENST00000911806, ENST00000911807, ENST00000911808, ENST00000911809, ENST00000911810, ENST00000911811, ENST00000911812, ENST00000943104, ENST00000943105, ENST00000943106, ENST00000943107, ENST00000943108, ENST00000943109, ENST00000943110, ENST00000943111, ENST00000943112, ENST00000943113, ENST00000943114, ENST00000943115, ENST00000943116

RefSeq mRNA: 10 — MANE Select: NM_000389 NM_000389, NM_001220777, NM_001220778, NM_001291549, NM_001374509, NM_001374510, NM_001374511, NM_001374512, NM_001374513, NM_078467

CCDS: CCDS4824

Canonical transcript exons

ENST00000244741 — 3 exons

Exon	Start	End
ENSE00001647673	36678714	36678798
ENSE00001952853	36685751	36687332
ENSE00003747087	36684097	36684546

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 441.6642 / max 5721.9343, expressed in 1821 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67533	436.5550	1819
67534	3.5240	1464
67529	0.8121	534
67530	0.6007	322
67528	0.1239	49
67531	0.0485	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.16	gold quality
mucosa of stomach	UBERON:0001199	99.14	gold quality
vena cava	UBERON:0004087	99.11	gold quality
left uterine tube	UBERON:0001303	98.98	gold quality
type B pancreatic cell	CL:0000169	98.96	gold quality
ascending aorta	UBERON:0001496	98.94	gold quality
thoracic aorta	UBERON:0001515	98.90	gold quality
aorta	UBERON:0000947	98.82	gold quality
saphenous vein	UBERON:0007318	98.81	gold quality
popliteal artery	UBERON:0002250	98.78	gold quality
tibial artery	UBERON:0007610	98.78	gold quality
descending thoracic aorta	UBERON:0002345	98.73	gold quality
mucosa of urinary bladder	UBERON:0001259	98.71	gold quality
skin of abdomen	UBERON:0001416	98.61	gold quality
gall bladder	UBERON:0002110	98.58	gold quality
lower esophagus mucosa	UBERON:0035834	98.57	gold quality
pericardium	UBERON:0002407	98.45	gold quality
nipple	UBERON:0002030	98.44	gold quality
omental fat pad	UBERON:0010414	98.44	gold quality
left ovary	UBERON:0002119	98.42	gold quality
peritoneum	UBERON:0002358	98.41	gold quality
right ovary	UBERON:0002118	98.40	gold quality
cervix squamous epithelium	UBERON:0006922	98.40	gold quality
mucosa of transverse colon	UBERON:0004991	98.26	gold quality
skin of leg	UBERON:0001511	98.23	gold quality
islet of Langerhans	UBERON:0000006	98.01	gold quality
coronary artery	UBERON:0001621	97.96	gold quality
left coronary artery	UBERON:0001626	97.96	gold quality
ectocervix	UBERON:0012249	97.93	gold quality
olfactory bulb	UBERON:0002264	97.81	silver quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	3702.38
E-GEOD-106540	yes	2091.71
E-MTAB-8498	yes	1275.53
E-MTAB-8530	yes	753.63
E-MTAB-10485	yes	742.48
E-MTAB-8205	yes	409.71
E-MTAB-6911	yes	398.46
E-CURD-46	yes	17.49
E-HCAD-10	yes	13.64
E-MTAB-9467	yes	12.45
E-MTAB-10553	yes	6.26
E-GEOD-99795	no	3696.40
E-MTAB-10137	no	1942.08
E-CURD-10	no	486.02
E-MTAB-9689	no	393.73

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
CDC25A	Repression
DNMT1	Repression
MYC	Repression

Upstream regulators (CollecTRI, top): AATF, ABL1, AHR, AP1, APEX1, AR, ARID1A, ARID3A, ARNT, ATF2, ATF3, ATM, BCCIP, BCL11B, BCL6, BHLHA15, BMAL1, BRCA1, CBX8, CDX2, CEBPA, CEBPB, CEBPG, CEBPZ, CREB1, CREBBP, CTCF, CTNNB1, CTNNBL1, CUX1, DDIT3, DDX5, DLX2, DMAP1, DMTF1, DNMT1, DNMT3A, DRAM2, E2F1, E2F2

miRNA regulators (miRDB)

99 targeting CDKN1A, 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-4283	100.00	66.42	2097
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4487	99.96	64.58	1252
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3663-3P	99.84	70.39	798

Literature-anchored findings (GeneRIF, showing 40)

• expression is related to apoptosis in thymus (PMID:11642719)
• p21CIP1/WAF1 was able to repress the immortal phenotype. CDKIs mediate growth arrest in human osteosarcoma cell lines and provides further evidence of the existence of molecular links between cellular mortality and immortality. (PMID:11695244)
• tested for inhibition of Plasmodium falciparum cyclin dependent protein kinases (PMID:11700040)
• In the ovarian cancer cell lines studied, cell growth was inhibited after transfection with p16(INK4a), p21(WAF1/Cip-1), and p53. (PMID:11733969)
• Cdk4 activity does correlate with changes in the level of the Cdk inhibitor p21(WAF1/Cip1 (PMID:11741909)
• induced after DNA damage and plays a role in cell survival (PMID:11748297)
• Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia. (PMID:11751405)
• The ability of p21(Cip1) to inhibit cyclin D1 nuclear export correlates with its ability to bind to Thr-286-phosphorylated cyclin D1 and thereby prevents cyclin D1.CRM1 association (PMID:11751903)
• phosphorylation by AKT/PKB enhances protein stability and promotes cell survival (PMID:11756412)
• expression inhibited by Hepatitis C virus core protein (PMID:11762751)
• expression in normal, hyperplastic and carcinomatous human prostate (PMID:11781193)
• Loss of the p21(Cip1/Waf1) cyclin kinase inhibitor results in propagation of horizontally transferred DNA. (PMID:11809712)
• hinge region of the human papillomavirus type 8 E2 protein activates the human p21(WAF1/CIP1) promoter via interaction with Sp1 (PMID:11842244)
• The expression of p21(WAF1/CIP1) was higher in the skin of arsenic intoxication than in controls. (PMID:11860939)
• We investigated three common sequence variants in TP53 and p21 for possible associations with the risk of breast cancer and with various phenotypic features of this disease (PMID:11872638)
• 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)
• The onset of ATRA-induced G(0)/G(1) arrest of U-937 cells is linked to an increase in p21(WAF1/CIP1) expression. (PMID:11877298)
• Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin (PMID:11877436)
• Specific inhibition of p21(Waf1/Cip1) protein with the antisense oligodeoxynucleotide markedly reduces the production and secretion of the matrix proteins fibronectin and laminin, both in the presence and absence of TGF-beta stimulation. (PMID:11882322)
• Early induction of CDKN1A (p21) and GADD45 mRNA by a low dose of ionizing radiation is due to their dose-dependent post-transcriptional regulation (PMID:11893252)
• REVIEW: gene expression regulation and role of CDK inhibitor P21 in cell survival and cell cycle control in early hematopoiesis. (PMID:11908736)
• Expression of p21WAF1 is dependent on the activation of ERK during vitamin E-succinate-induced monocytic differentiation. (PMID:11911463)
• Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1). (PMID:11943869)
• cyclooxygenase-2 inhibitor induces G0/G1 cell cycle arrest in NA cells by upregulation of p21 (PMID:11953864)
• expression in pelvic lymph nodes and primary tumors in early stage cervical carcinomas (PMID:11956602)
• Correlation of p21 gene codon 31 polymorphism and TNF-alpha gene polymorphism with nasopharyngeal carcinoma. (PMID:11968052)
• Results suggest that p21(Cip/WAF1) and cyclin D1 induction may result from the activation of the ERK and PI-3 kinase pathways. (PMID:11989975)
• A strong inhibition of cell proliferation was observed in K562-p21(WAF1) cell as compared with that of the control, and the cell number in G(0)/G(1) phase was remarkably increased. (PMID:12015083)
• interferon-alpha exerts antitumor effects by increased p21 expression in neuroendocrine tumors (PMID:12025230)
• Review of the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors. (PMID:12046058)
• Cell attachment to the extracellular matrix induces proteasomal degradation of p21(CIP1) via Cdc42/Rac1 signaling (P21CIP1) (PMID:12052868)
• H(2)O(2)-induced AP-1 activation and its effect on p21(WAF1/CIP1)-mediated G2/M arrest in a p53-deficient human lung cancer cell. (PMID:12054510)
• Identification of the regulatory region required for ubiquitination of the cyclin kinase inhibitor, p21. (PMID:12054572)
• Oxidized low density lipoprotein induces the cyclin-dependent kinase inhibitor p21(waf1) and the tumor suppressor Rb. (PMID:12054658)
• results suggested that p21 is up-regulated by the stress of inflammation and fibrosis in hepatitis C virus (HCV)-associated chronic liver diseases and that high p21 expression might be related to hepatocarcinogenesis in cirrhotic patients (PMID:12055678)
• stabilization by phosphorylation influenzed by protein kinase p38 alpha and JNK1 (PMID:12058028)
• p21/WAF1 expression associated with endocrine activity in pituitary adenomas; tumors expressing cytoplasmic p21/WAF1 may have resistance to DNA-damaging agents such as ionizing radiation (PMID:12111504)
• P27Kip1 immunoreactivity is higher in male breast cancers compared with female breast cancers. (PMID:12123335)
• transcriptional regulation of p21 CIP1 WAF1 controls p53 independent ovarian cancer apoptosis (PMID:12138103)
• C/EBPalpha is essential for p21-mediated inhibition of G1 to S-phase progression by RAP in KSHV-infected host cells (PMID:12145325)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdkn1a	ENSDARG00000076554
mus_musculus	Cdkn1a	ENSMUSG00000023067
rattus_norvegicus	Cdkn1a	ENSRNOG00000000521

Paralogs (2): CDKN1B (ENSG00000111276), CDKN1C (ENSG00000129757)

Protein

Protein identifiers

Cyclin-dependent kinase inhibitor 1 — P38936 (reviewed: P38936)

Alternative names: CDK-interacting protein 1, Melanoma differentiation-associated protein 6, p21

All UniProt accessions (1): P38936

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in controlling cell cycle progression and DNA damage-induced G2 arrest. Involved in p53/TP53 mediated inhibition of cellular proliferation in response to DNA damage. Also involved in p53-independent DNA damage-induced G2 arrest mediated by CREB3L1 in astrocytes and osteoblasts. Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression. Functions in the nuclear localization and assembly of cyclin D-CDK4 complex and promotes its kinase activity towards RB1. At higher stoichiometric ratios, inhibits the kinase activity of the cyclin D-CDK4 complex. Inhibits DNA synthesis by DNA polymerase delta by competing with POLD3 for PCNA binding. Negatively regulates the CDK4- and CDK6-driven phosphorylation of RB1 in keratinocytes, thereby resulting in the release of E2F1 and subsequent transcription of E2F1-driven G1/S phase promoting genes.

Subunit / interactions. Interacts with HDAC1; the interaction is prevented by competitive binding of C10orf90/FATS to HDAC1 facilitating acetylation and protein stabilization of CDKN1A/p21. Interacts with MKRN1. Interacts with PSMA3. Interacts with PCNA. Component of the ternary complex, cyclin D-CDK4-CDKN1A. Interacts (via its N-terminal domain) with CDK4; the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4. Binding to CDK2 leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair. Interacts with PIM1. Interacts with STK11 and NUAK1. Interacts wih DTL. Interacts with isoform 1 and isoform 2 of TRIM39. Interacts with PKP3; the interaction sequesters CDKN1A to the cytoplasm thereby repressing its role as an inhibitor of CDK4- and CDK6-driven RB1 phosphorylation.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in all adult tissues, with 5-fold lower levels observed in the brain.

Post-translational modifications. Phosphorylation of Thr-145 by Akt or of Ser-146 by PKC impairs binding to PCNA. Phosphorylation at Ser-114 by GSK3-beta enhances ubiquitination by the DCX(DTL) complex. Phosphorylation of Thr-145 by PIM2 enhances CDKN1A stability and inhibits cell proliferation. Phosphorylation of Thr-145 by PIM1 results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. UV radiation-induced phosphorylation at Thr-80 by LKB1 and at Ser-146 by NUAK1 leads to its degradation. Ubiquitinated by MKRN1; leading to polyubiquitination and 26S proteasome-dependent degradation. Ubiquitinated by the DCX(DTL) complex, also named CRL4(CDT2) complex, leading to its degradation during S phase or following UV irradiation. Ubiquitination by the DCX(DTL) complex is essential to control replication licensing and is PCNA-dependent: interacts with PCNA via its PIP-box, while the presence of the containing the ‘K+4’ motif in the PIP box, recruit the DCX(DTL) complex, leading to its degradation. Ubiquitination at Ser-2 leads to degradation by the proteasome pathway. Ubiquitinated by RNF114; leading to proteasomal degradation. Acetylation leads to protein stability. Acetylated in vitro on Lys-141, Lys-154, Lys-161 and Lys-163. Deacetylation by HDAC1 is prevented by competitive binding of C10orf90/FATS to HDAC1.

Domain organisation. The PIP-box K+4 motif mediates both the interaction with PCNA and the recruitment of the DCX(DTL) complex: while the PIP-box interacts with PCNA, the presence of the K+4 submotif, recruits the DCX(DTL) complex, leading to its ubiquitination. The C-terminal is required for nuclear localization of the cyclin D-CDK4 complex.

Induction. Activated by p53/TP53, mezerein (antileukemic compound) and IFNB1. Repressed by HDAC1.

Similarity. Belongs to the CDI family.

RefSeq proteins (10): NP_000380, NP_001207706, NP_001207707, NP_001278478, NP_001361438, NP_001361439, NP_001361440, NP_001361441, NP_001361442, NP_510867 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003175	CDI_dom	Domain
IPR029841	CDKN1A	Family
IPR044898	CDI_dom_sf	Homologous_superfamily

Pfam: PF02234

UniProt features (38 total): mutagenesis site 10, modified residue 7, region of interest 4, strand 4, sequence variant 3, helix 2, short sequence motif 2, initiator methionine 1, chain 1, cross-link 1, zinc finger region 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
5E0U	X-RAY DIFFRACTION	1.93
2ZVV	X-RAY DIFFRACTION	2
8GJF	X-RAY DIFFRACTION	2
4RJF	X-RAY DIFFRACTION	2.01
7KQ0	X-RAY DIFFRACTION	2.4
2ZVW	X-RAY DIFFRACTION	2.5
1AXC	X-RAY DIFFRACTION	2.6
6CBI	X-RAY DIFFRACTION	2.75
6P8H	X-RAY DIFFRACTION	3.19
7KQ1	X-RAY DIFFRACTION	3.3
6CEJ	SOLUTION NMR
6CIV	SOLUTION NMR
6CIX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P38936-F1	70.16	0.29

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): 2, 80, 114, 130, 145, 146, 160, 2

Mutagenesis-validated functional residues (10):

Position	Phenotype
80	abolishes uv radiation-induced phosphorylation and subsequent degradation.
114	phosphomimetic mutant, increases ubiquitination by the dcx(dtl) complex.
144–150	abolishes interaction with pcna and subsequent degradation by the proteasome.
145	reduces phosphorylation by akt; no change in interaction with pcna, cdk2 or cdk4; no change in subcellular location.
145	no interaction with pcna; 59% inhibition of cdk2 binding; modest inhibition of cdk4 binding; no change in subcellular lo
146	no change in interaction with pcna. abolishes uv radiation-induced phosphorylation and subsequent degradation.
146	reduces interaction with pcna.
147–151	abolishes interaction with pcna and subsequent degradation by the proteasome.
154–156	abolishes degradation by the proteasome without affecting the interaction with pcna.
154	loss of interaction with trim39.

Function

Pathways and Gene Ontology

Reactome pathways

70 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-5674400	Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
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-69895	Transcriptional activation of cell cycle inhibitor p21
R-HSA-8852276	The role of GTSE1 in G2/M progression after G2 checkpoint
R-HSA-8866911	TFAP2 (AP-2) family regulates transcription of cell cycle factors
R-HSA-8878166	Transcriptional regulation by RUNX2
R-HSA-8941855	RUNX3 regulates CDKN1A transcription
R-HSA-8951664	Neddylation
R-HSA-9616222	Transcriptional regulation of granulopoiesis
R-HSA-9617828	FOXO-mediated transcription of cell cycle genes
R-HSA-9661069	Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)
R-HSA-9702518	STAT5 activation downstream of FLT3 ITD mutants
R-HSA-9703465	Signaling by FLT3 fusion proteins
R-HSA-9725370	Signaling by ALK fusions and activated point mutants
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-9825892	Regulation of MITF-M-dependent genes involved in cell cycle and proliferation
R-HSA-2559584	Formation of Senescence-Associated Heterochromatin Foci (SAHF)
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction

MSigDB gene sets: 998 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, SA_G2_AND_M_PHASES, WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, MODULE_52, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, AP1_01, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, FREAC2_01, HNF3ALPHA_Q6, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, HARRIS_HYPOXIA

GO Biological Process (53): G1/S transition of mitotic cell cycle (GO:0000082), in utero embryonic development (GO:0001701), protein import into nucleus (GO:0006606), DNA damage response (GO:0006974), mitotic G2 DNA damage checkpoint signaling (GO:0007095), Ras protein signal transduction (GO:0007265), heart development (GO:0007507), negative regulation of cell population proliferation (GO:0008285), regulation of G2/M transition of mitotic cell cycle (GO:0010389), negative regulation of gene expression (GO:0010629), keratinocyte differentiation (GO:0030216), negative regulation of cell growth (GO:0030308), DNA damage response, signal transduction by p53 class mediator (GO:0030330), positive regulation of B cell proliferation (GO:0030890), mitotic G1 DNA damage checkpoint signaling (GO:0031571), cellular response to amino acid starvation (GO:0034198), wound healing (GO:0042060), tissue regeneration (GO:0042246), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), positive regulation of programmed cell death (GO:0043068), keratinocyte proliferation (GO:0043616), positive regulation of DNA replication (GO:0045740), positive regulation of protein kinase activity (GO:0045860), fibroblast proliferation (GO:0048144), positive regulation of fibroblast proliferation (GO:0048146), import into nucleus (GO:0051170), regulation of cell cycle (GO:0051726), cellular response to cell-matrix adhesion (GO:0071460), cellular response to ionizing radiation (GO:0071479), cellular response to gamma radiation (GO:0071480), cellular response to UV-B (GO:0071493), cellular senescence (GO:0090398), replicative senescence (GO:0090399), stress-induced premature senescence (GO:0090400), oncogene-induced cell senescence (GO:0090402), intrinsic apoptotic signaling pathway (GO:0097193), regulation of cell cycle G1/S phase transition (GO:1902806), 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)

GO Molecular Function (14): protein kinase inhibitor activity (GO:0004860), cyclin-dependent protein serine/threonine kinase inhibitor activity (GO:0004861), zinc ion binding (GO:0008270), protein kinase binding (GO:0019901), cyclin binding (GO:0030332), ubiquitin protein ligase binding (GO:0031625), protein-containing complex binding (GO:0044877), protein serine/threonine kinase binding (GO:0120283), protein sequestering activity (GO:0140311), molecular function activator activity (GO:0140677), molecular function inhibitor activity (GO:0140678), protein binding (GO:0005515), obsolete cyclin-dependent protein kinase activating kinase activity (GO:0019912), metal ion binding (GO:0046872)

GO Cellular Component (9): cyclin-dependent protein kinase holoenzyme complex (GO:0000307), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear body (GO:0016604), protein-containing complex (GO:0032991), PCNA-p21 complex (GO:0070557)

Reactome top-level categories

Rollup of top-20 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
PI3K/AKT Signaling in Cancer	1
Signaling by Interleukins	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
Transcriptional activation of p53 responsive genes	1
G2/M Transition	1
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
mitotic DNA damage checkpoint signaling	2
negative regulation of cellular process	2
protein binding	2
binding	2
molecular function regulator activity	2
nuclear lumen	2
intracellular membraneless organelle	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
chordate embryonic development	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
cellular response to stress	1
mitotic G2 phase	1
mitotic G2/M transition checkpoint	1
small GTPase-mediated signal transduction	1
animal organ development	1
circulatory system development	1
cell population proliferation	1
regulation of cell population proliferation	1
G2/M transition of mitotic cell cycle	1
regulation of mitotic cell cycle phase transition	1
regulation of cell cycle G2/M phase transition	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
epidermal cell differentiation	1
skin development	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
regulation of B cell proliferation	1
B cell proliferation	1
positive regulation of lymphocyte proliferation	1

Protein interactions and networks

STRING

5536 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDKN1A	CDK2	P24941	999
CDKN1A	CDK4	P11802	998
CDKN1A	CCND1	P24385	996
CDKN1A	CCNA1	P78396	996
CDKN1A	CCNL2	Q96S94	996
CDKN1A	CCNA2	P20248	996
CDKN1A	CDK6	Q00534	995
CDKN1A	FOXO3	O43524	994
CDKN1A	CDK1	P06493	987
CDKN1A	CIZ1	Q9ULV3	987
CDKN1A	BCCIP	Q9P287	976
CDKN1A	TP53	P04637	961
CDKN1A	CDKN3	Q16667	947
CDKN1A	E2F1	Q01094	947
CDKN1A	MYC	P01106	945

IntAct

515 interactions, top by confidence:

A	B	Type	Score
CDKN1A	PCNA	psi-mi:“MI:0915”(physical association)	0.980
PCNA	CDKN1A	psi-mi:“MI:0915”(physical association)	0.980
CDK2	CDKN1A	psi-mi:“MI:0915”(physical association)	0.980
CDKN1A	CDK2	psi-mi:“MI:0915”(physical association)	0.980
CDK2	CDKN1A	psi-mi:“MI:0407”(direct interaction)	0.980
PCNA	CDKN1A	psi-mi:“MI:0407”(direct interaction)	0.980
CDK2	CDKN1A	psi-mi:“MI:0914”(association)	0.980
CDKN1A	CDK2	psi-mi:“MI:0914”(association)	0.980
CDKN1A	PCNA	psi-mi:“MI:0407”(direct interaction)	0.980

BioGRID (923): CDKN1A (Affinity Capture-Western), CDKN1A (Biochemical Activity), CDKN1A (Affinity Capture-Western), CDKN1A (Two-hybrid), CDKN1A (Two-hybrid), CDKN1A (Two-hybrid), KRT31 (Two-hybrid), PCNA (Two-hybrid), TCF4 (Two-hybrid), TRAF1 (Two-hybrid), IKZF3 (Two-hybrid), TEX11 (Two-hybrid), TRIM54 (Two-hybrid), PCNA (Reconstituted Complex), PCNA (Affinity Capture-Western)

ESM2 similar proteins: A2AI08, A6QLA6, O19001, O19002, O94992, P38936, P39689, P46414, P46527, P46529, Q0X0C4, Q13111, Q1LZD3, Q2WG78, Q3KP66, Q4FZR5, Q58CQ0, Q5BJT1, Q5EE38, Q5M9G1, Q5SX79, Q5XHX2, Q5XIB1, Q60439, Q68DK7, Q69YU3, Q6AYH4, Q6NSI3, Q6PDM1, Q6PGN9, Q6SLL5, Q7TN12, Q80Y50, Q86WR7, Q8BHZ5, Q8BY98, Q8C0J6, Q8CFU8, Q8CHM3, Q8IXH6

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

SIGNOR signaling

94 interactions.

A	Effect	B	Mechanism
MYC	“down-regulates quantity by repression”	CDKN1A	“transcriptional regulation”
RBPJ	“up-regulates quantity by expression”	CDKN1A	“transcriptional regulation”
CDKN1A	down-regulates	CDK1	binding
SKP2	down-regulates	CDKN1A	ubiquitination
PRKCA	“up-regulates activity”	CDKN1A	phosphorylation
CDK6	“down-regulates activity”	CDKN1A	phosphorylation
CDK2	“down-regulates quantity by destabilization”	CDKN1A	phosphorylation
AKT1	“up-regulates quantity by stabilization”	CDKN1A	phosphorylation
AKT2	“down-regulates activity”	CDKN1A	binding
CDKN1A	down-regulates	CDK2	binding
GSK3B	“down-regulates quantity by destabilization”	CDKN1A	phosphorylation
MAP3K5	up-regulates	CDKN1A	phosphorylation
MDM2	“down-regulates quantity by repression”	CDKN1A
PIM1	“up-regulates quantity by stabilization”	CDKN1A	phosphorylation
PIM2	“up-regulates quantity by stabilization”	CDKN1A	phosphorylation
MAGED1	up-regulates	CDKN1A
TP53	“up-regulates quantity by expression”	CDKN1A	“transcriptional regulation”
PBRM1	“up-regulates quantity by expression”	CDKN1A	“transcriptional regulation”
CDKN1A	down-regulates	CCNB1	binding
MAPK1	“down-regulates quantity by destabilization”	CDKN1A	phosphorylation
PRKAA1	“down-regulates quantity by repression”	CDKN1A	“transcriptional regulation”
CDKN1A	down-regulates	PCNA	binding
AKT	“up-regulates quantity by stabilization”	CDKN1A	phosphorylation
AKT	“down-regulates activity”	CDKN1A	binding
ERK1/2	“down-regulates quantity by destabilization”	CDKN1A	phosphorylation
CDKN1A	“down-regulates activity”	CyclinE/CDK2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 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)	9	139.3×	1e-15
TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest	5	87.0×	6e-08
p53-Dependent G1 DNA Damage Response	5	87.0×	6e-08
p53-Dependent G1/S DNA damage checkpoint	5	87.0×	6e-08
G1/S DNA Damage Checkpoints	5	81.9×	7e-08
Aberrant regulation of mitotic cell cycle due to RB1 defects	8	79.6×	4e-12
TP53 Regulates Transcription of Cell Cycle Genes	6	79.6×	3e-09
G1 Phase	8	76.8×	4e-12

GO biological processes:

GO term	Partners	Fold	FDR
G1/S transition of mitotic cell cycle	14	54.0×	2e-18
positive regulation of G1/S transition of mitotic cell cycle	5	38.6×	2e-05
cell division	17	15.1×	1e-13
Wnt signaling pathway	5	9.6×	8e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 3 cancer types — BLCA, CHRCC, HCC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	21
Likely benign	11
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2582285	NM_000389.5(CDKN1A):c.142C>T (p.Arg48Ter)	Pathogenic

SpliceAI

1017 predictions. Top by Δscore:

Variant	Effect	Δscore
6:36684423:G:GT	donor_gain	1.0000
6:36684092:T:A	acceptor_gain	0.9900
6:36684093:GCA:G	acceptor_loss	0.9900
6:36684094:CA:C	acceptor_loss	0.9900
6:36684095:A:AG	acceptor_gain	0.9900
6:36684096:G:GA	acceptor_loss	0.9900
6:36684096:G:GG	acceptor_gain	0.9900
6:36684096:GGC:G	acceptor_gain	0.9900
6:36684231:G:GT	donor_gain	0.9900
6:36684279:G:GT	donor_gain	0.9900
6:36684280:A:T	donor_gain	0.9900
6:36684296:G:GT	donor_gain	0.9900
6:36684298:A:T	donor_gain	0.9900
6:36684360:GA:G	donor_gain	0.9900
6:36684089:T:TA	acceptor_gain	0.9800
6:36684095:AGGC:A	acceptor_gain	0.9800
6:36684096:GGCG:G	acceptor_gain	0.9800
6:36684281:GG:G	donor_gain	0.9800
6:36684282:GG:G	donor_gain	0.9800
6:36684359:GGA:G	donor_gain	0.9800
6:36684564:G:GT	donor_gain	0.9700
6:36684095:AG:A	acceptor_gain	0.9600
6:36684096:GG:G	acceptor_gain	0.9600
6:36684233:GGCCC:G	donor_gain	0.9600
6:36684234:GCCCG:G	donor_gain	0.9600
6:36684361:A:G	donor_gain	0.9600
6:36684473:G:T	donor_gain	0.9600
6:36684489:TCCCC:T	donor_gain	0.9600
6:36685745:CCTCA:C	acceptor_loss	0.9600
6:36685746:CTCAG:C	acceptor_loss	0.9600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000096520 (6:36678255 T>A,C), RS1000834944 (6:36681325 T>C), RS1000963720 (6:36681119 C>T), RS1001435130 (6:36687673 A>G,T), RS1001805922 (6:36681873 T>C), RS1002140591 (6:36675781 G>C), RS1002260135 (6:36686196 C>A,T), RS1002279958 (6:36678967 G>A), RS1002289641 (6:36686541 C>T), RS1002314083 (6:36678709 C>T), RS1002546307 (6:36680735 C>A), RS1002643052 (6:36685367 G>C), RS1002649716 (6:36679883 A>G), RS1002737804 (6:36685066 C>A), RS1003290514 (6:36674694 T>C)

Disease associations

OMIM: gene MIM:116899 | disease phenotypes: MIM:109800

GenCC curated gene-disease

Mondo (1): urinary bladder cancer (MONDO:0001187)

Orphanet (1): NON RARE IN EUROPE: Bladder cancer (Orphanet:157980)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3038463 (PROTEIN COMPLEX), CHEMBL5021 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items; also 2 predisposing.

Variant	Therapy	Indication	Effect	Level	CIViC
CDKN1A EXPRESSION	Fluorouracil	Colorectal Cancer	Resistance	CIViC B	EID852

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

ChEMBL bioactivities

14 potent at pChembl≥5 of 17 total, top 14 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.77	IC50	170	nM	CHEMBL5277005
6.40	IC50	400	nM	CHEMBL368233
6.31	IC50	490	nM	CHEMBL5266126
6.19	IC50	640	nM	CHEMBL4226806
6.17	IC50	680	nM	CHEMBL179694
6.12	IC50	750	nM	CHEMBL178807
6.12	IC50	760	nM	CHEMBL1434157
5.64	IC50	2300	nM	CHEMBL179730
5.62	IC50	2400	nM	CHEMBL179110
5.62	IC50	2400	nM	CHEMBL178310
5.46	IC50	3500	nM	CHEMBL425866
5.39	IC50	4100	nM	CHEMBL179916
5.18	IC50	6600	nM	CHEMBL178807
5.08	IC50	8400	nM	CHEMBL179178

PubChem BioAssay actives

14 with measured affinity, of 95 total; 13 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[3-[(6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)methyl]phenyl]ethanone	1933425: Inhibition of p21 (unknown origin)	ic50	0.1700	uM
N-[3-[3-(thiophene-2-carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl]phenyl]cyclopropanecarboxamide	248292: Inhibitory concentration against p21 deficient cell (p21-/-) proliferation	ic50	0.4000	uM
N-(5-benzamido-2-phenyl-1,2,4-triazol-3-yl)-4-methoxybenzamide	1933425: Inhibition of p21 (unknown origin)	ic50	0.4900	uM
4-(2-phenylethylamino)quinazoline-6-carbonitrile	1388680: Inhibition of p21 (unknown origin)-induced transcription in human HT1080 p21-9-CMV-GFP cells after 3 days by fluorescence assay	ic50	0.6400	uM
2-(2-fluoro-4-methoxyphenyl)-5,6,7,8-tetrahydro-3H-[1]benzothiolo[2,3-d]pyrimidin-4-one	248292: Inhibitory concentration against p21 deficient cell (p21-/-) proliferation	ic50	0.6800	uM
5-(3,4,5-trimethoxyphenyl)-8-thia-4,6-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),5-trien-3-one	248292: Inhibitory concentration against p21 deficient cell (p21-/-) proliferation	ic50	0.7500	uM
ethyl 4-[[5-(2,3-dimethylanilino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-6-yl]amino]benzoate	1933425: Inhibition of p21 (unknown origin)	ic50	0.7600	uM
2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-[1]benzothiolo[2,3-d]pyrimidin-4-one	248292: Inhibitory concentration against p21 deficient cell (p21-/-) proliferation	ic50	2.3000	uM
10-(4-methoxyphenyl)-7-thia-9,11-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9-trien-12-one	248292: Inhibitory concentration against p21 deficient cell (p21-/-) proliferation	ic50	2.4000	uM
2-(4-methoxyphenyl)-5,6,7,8-tetrahydro-3H-[1]benzothiolo[2,3-d]pyrimidin-4-one	248292: Inhibitory concentration against p21 deficient cell (p21-/-) proliferation	ic50	2.4000	uM
10-(3,4,5-trimethoxyphenyl)-7-thia-9,11-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9-trien-12-one	248292: Inhibitory concentration against p21 deficient cell (p21-/-) proliferation	ic50	3.5000	uM
2-(4-methylsulfanylphenyl)-5,6,7,8-tetrahydro-3H-[1]benzothiolo[2,3-d]pyrimidin-4-one	248292: Inhibitory concentration against p21 deficient cell (p21-/-) proliferation	ic50	4.1000	uM
2-(4-ethoxyphenyl)-5,6,7,8-tetrahydro-3H-[1]benzothiolo[2,3-d]pyrimidin-4-one	248292: Inhibitory concentration against p21 deficient cell (p21-/-) proliferation	ic50	8.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	decreases reaction, increases expression, decreases expression, affects binding, increases activity (+4 more)	49
Cisplatin	decreases expression, decreases reaction, increases reaction, increases activity, increases phosphorylation (+8 more)	44
Doxorubicin	decreases expression, increases expression, affects expression, affects reaction, affects response to substance (+7 more)	44
Benzo(a)pyrene	increases expression, increases reaction, affects expression, affects methylation, decreases expression (+9 more)	40
Arsenic Trioxide	increases phosphorylation, increases stability, increases sumoylation, increases response to substance, affects reaction (+9 more)	39
sodium arsenite	increases phosphorylation, increases abundance, affects response to substance, affects cotreatment, affects expression (+5 more)	35
Fluorouracil	decreases reaction, affects response to substance, affects binding, affects reaction, decreases expression (+6 more)	31
Vorinostat	increases cleavage, increases expression, increases reaction, affects localization, decreases expression (+1 more)	28
Hydrogen Peroxide	affects localization, increases reaction, decreases reaction, increases expression, affects reaction (+4 more)	23
Quercetin	affects cotreatment, increases expression, increases reaction, increases stability, affects reaction (+4 more)	23
Decitabine	increases reaction, affects expression, decreases methylation, increases activity, decreases reaction (+7 more)	22
Estradiol	decreases expression, decreases reaction, increases reaction, increases expression, increases secretion (+4 more)	22
Tretinoin	affects cotreatment, increases expression, affects activity, increases activity, decreases expression (+3 more)	22
(+)-JQ1 compound	increases reaction, affects response to substance, affects expression, affects cotreatment, increases expression (+2 more)	20
Etoposide	increases response to substance, affects cotreatment, decreases reaction, increases activity, affects reaction (+3 more)	20
trichostatin A	affects expression, increases expression, increases reaction, decreases reaction, affects reaction (+1 more)	18
Bortezomib	increases reaction, increases stability, affects reaction, decreases response to substance, affects cotreatment (+2 more)	18
Acetylcysteine	decreases reaction, increases expression, decreases expression, affects binding, increases reaction	15
Curcumin	affects reaction, increases expression, increases activity, decreases expression, increases reaction (+3 more)	15
bisphenol A	decreases expression, affects expression, affects reaction, affects cotreatment, increases expression (+1 more)	14
Troglitazone	decreases reaction, increases expression, affects cotreatment, affects binding, increases reaction (+4 more)	14
Calcitriol	increases abundance, affects cotreatment, increases expression, decreases expression, decreases reaction	14
Tetrachlorodibenzodioxin	decreases activity, decreases response to substance, decreases reaction, affects reaction, increases reaction (+4 more)	14
Cadmium Chloride	increases abundance, increases expression, affects reaction, decreases reaction, affects cotreatment (+2 more)	14
Particulate Matter	increases stability, decreases reaction, increases expression, increases abundance, increases reaction (+9 more)	14
Valproic Acid	increases reaction, affects cotreatment, decreases reaction, affects expression, decreases methylation (+1 more)	13
Genistein	increases expression, affects reaction, decreases expression, decreases reaction, increases phosphorylation (+1 more)	13
pifithrin	increases expression, increases abundance, decreases activity, increases reaction, decreases expression (+2 more)	12
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases expression, increases reaction, increases phosphorylation, affects localization, decreases reaction	11
nutlin 3	increases secretion, affects reaction, increases expression, decreases expression, decreases reaction (+3 more)	10

ChEMBL screening assays

16 unique, capped per target: 8 binding, 8 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2423501	Binding	Inhibition of AKT/p21CIP1 in human DU145 cells assessed as decrease in ratio of phosphorylated retinoblastoma level to unphosphorylated retinoblastoma level at 0.1 uM after 72 hrs by Western blotting analysis	Antitumor properties of substituted (αE)-α-(1H-indol-3-ylmethylene)benzeneacetic acids or amides. — Bioorg Med Chem
CHEMBL827456	Functional	Selectivity ratio between p21(-/-) and p21(+/+) isogenic cell lines	Inhibition of tumor cell proliferation by thieno[2,3-d]pyrimidin-4(1H)-one-based analogs. — Bioorg Med Chem Lett

Cellosaurus cell lines

18 cell lines: 17 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1DA	Abcam HCT 116 CDKN1A KO 1	Cancer cell line	Male
CVCL_B1N7	Abcam HeLa CDKN1A KO	Cancer cell line	Female
CVCL_B8AN	Abcam HCT 116 CDKN1A KO 2	Cancer cell line	Male
CVCL_B8TZ	Abcam MCF-7 CDKN1A KO	Cancer cell line	Female
CVCL_B9FP	Abcam A-549 CDKN1A KO	Cancer cell line	Male
CVCL_D7MD	Ubigene A-549 CDKN1A KO	Cancer cell line	Male
CVCL_D8IT	Ubigene HCT 116 CDKN1A KO	Cancer cell line	Male
CVCL_D9BR	Ubigene HEK293 CDKN1A KO	Transformed cell line	Female
CVCL_D9ZX	Ubigene HeLa CDKN1A KO	Cancer cell line	Female
CVCL_HD58	DLD-1 CDKN1A(-/-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00384891	PHASE3	TERMINATED	Hyperthermia Treatment in Conjunction With Mitomycin C Versus Bacillus Calmette-Guérin Immunotherapy (BCG) for Superficial Bladder Cancer
NCT03335059	PHASE3	TERMINATED	Mitomycin C Intravesical Chemotherapy in Conjunction With Synergo® Radiofrequency-Induced Hyperthermia for Treatment of Carcinoma in Situ Non-Muscle Invasive Bladder Cancer Patients Unresponsive to Bacillus Calmette-Guérin, With or Without Papillary Tumors.
NCT04534075	PHASE3	COMPLETED	Dietary Fiber During Radiotherapy - a Placebo-controlled Randomized Trial
NCT05822934	PHASE3	ACTIVE_NOT_RECRUITING	Carboplatin-gemcitabine Versus Cisplatin- Gemcitabine as Neoadjuvant Chemotherapy for Treatment of Muscle Invasive Urinary Bladder Cancer
NCT00462488	PHASE2	COMPLETED	Study of Vicinium for Treating Patients With Non-Invasive Urothelial Carcinoma In Situ
NCT01374789	PHASE2	TERMINATED	PURO Panitumumab in Combination With Gemcitabine/Cisplatin in Advanced Urothelial Cancer
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