CREBL2

Summary

CREBL2 (cAMP responsive element binding protein like 2, HGNC:2350) is a protein-coding gene on chromosome 12p13.1, encoding cAMP-responsive element-binding protein-like 2 (O60519). Probable regulator of CREB1 transcriptional activity which is involved in adipose cells differentiation.

cAMP response element (CRE)-binding protein-like-2 (CREBL2) was identified in a search to find genes in a commonly deleted region on chromosome 12p13 flanked by ETV6 and CDKN1B genes, frequently associated with hematopoietic malignancies, as well as breast, non-small-cell lung and ovarian cancers. CREBL2 shares a 41% identity with CRE-binding protein (CREB) over a 48-base long region which encodes the bZip domain of CREB. The bZip domain consists of about 30 amino acids rich in basic residues involved in DNA binding, followed by a leucine zipper motif involved in protein dimerization. This suggests that CREBL2 encodes a protein with DNA binding capabilities. The occurance of CREBL2 deletion in malignancy suggests that CREBL2 may act as a tumor suppressor gene.

Source: NCBI Gene 1389 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 19 total — 1 likely-pathogenic
• MANE Select transcript: NM_001310

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2350
Approved symbol	CREBL2
Name	cAMP responsive element binding protein like 2
Location	12p13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000111269
Ensembl biotype	protein_coding
OMIM	603476
Entrez	1389

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000228865, ENST00000540224, ENST00000893303, ENST00000965829

RefSeq mRNA: 1 — MANE Select: NM_001310 NM_001310

CCDS: CCDS8651

Canonical transcript exons

ENST00000228865 — 4 exons

Exon	Start	End
ENSE00000822051	12637570	12637714
ENSE00001217365	12641994	12645108
ENSE00001217372	12611876	12612187
ENSE00003604746	12635777	12635974

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.6988 / max 304.3972, expressed in 1805 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124331	25.9900	1800
124333	2.0399	881
124334	1.7303	509
124332	0.6043	333
124335	0.3342	119

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	98.35	gold quality
parietal pleura	UBERON:0002400	98.07	gold quality
pleura	UBERON:0000977	97.72	gold quality
caput epididymis	UBERON:0004358	97.46	gold quality
right adrenal gland cortex	UBERON:0035827	97.42	gold quality
visceral pleura	UBERON:0002401	97.36	gold quality
corpus epididymis	UBERON:0004359	97.29	gold quality
right adrenal gland	UBERON:0001233	97.22	gold quality
pigmented layer of retina	UBERON:0001782	97.19	gold quality
retina	UBERON:0000966	97.16	gold quality
adrenal cortex	UBERON:0001235	97.16	gold quality
left adrenal gland	UBERON:0001234	97.08	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.06	gold quality
left adrenal gland cortex	UBERON:0035825	97.02	gold quality
nephron tubule	UBERON:0001231	97.00	gold quality
superficial temporal artery	UBERON:0001614	96.86	gold quality
cranial nerve II	UBERON:0000941	96.78	gold quality
tibia	UBERON:0000979	96.71	gold quality
middle temporal gyrus	UBERON:0002771	96.58	gold quality
adrenal gland	UBERON:0002369	96.56	gold quality
choroid plexus epithelium	UBERON:0003911	96.54	gold quality
endothelial cell	CL:0000115	96.36	gold quality
pons	UBERON:0000988	96.21	gold quality
lower lobe of lung	UBERON:0008949	95.97	gold quality
renal glomerulus	UBERON:0000074	95.95	gold quality
upper leg skin	UBERON:0004262	95.79	gold quality
adult organism	UBERON:0007023	95.72	gold quality
olfactory bulb	UBERON:0002264	95.60	gold quality
parotid gland	UBERON:0001831	95.59	gold quality
metanephric glomerulus	UBERON:0004736	95.59	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.16

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CEBPA	Activation
PPARG	Activation

miRNA regulators (miRDB)

195 targeting CREBL2, 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-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 2)

• Data indicate that LRP6, BCL2L14, DUSP16, CREBL2, and CDKN1B were involed in centromeric (12p11.21-12p13.2) deletion in ETV6-RUNX1 B-cell precursor acute lymphoblastic leukemia (BCP-ALL). (PMID:23077088)
• Parathyroid hormone receptor-1 signaling aggravates hepatic fibrosis through upregulating cAMP response element-binding protein-like 2. (PMID:36939197)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	crebl2	ENSDARG00000104049
mus_musculus	Crebl2	ENSMUSG00000032652
rattus_norvegicus	Crebl2	ENSRNOG00000067300
drosophila_melanogaster	REPTOR-BP	FBGN0032202

Protein

Protein identifiers

cAMP-responsive element-binding protein-like 2 — O60519 (reviewed: O60519)

All UniProt accessions (1): O60519

UniProt curated annotations — full annotation on UniProt →

Function. Probable regulator of CREB1 transcriptional activity which is involved in adipose cells differentiation. May also play a regulatory role in the cell cycle. Identification in a chromosomal region frequently deleted in various cancers suggests that it might act as a tumor suppressor.

Subunit / interactions. Interacts with CREB1; regulates CREB1 phosphorylation, stability and transcriptional activity.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylated by AMPK.

Similarity. Belongs to the bZIP family. ATF subfamily.

RefSeq proteins (1): NP_001301* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004827	bZIP	Domain
IPR039250	CREBL2/REPTOR-BP	Family
IPR046347	bZIP_sf	Homologous_superfamily

Pfam: PF07716

UniProt features (7 total): region of interest 4, chain 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60519-F1	76.59	0.48

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 316 (showing top): GCACCTT_MIR18A_MIR18B, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, FREAC2_01, MYOGENIN_Q6, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_POSITIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_PEPTIDYL_SERINE_MODIFICATION, FOXO4_01, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_PEPTIDYL_SERINE_PHOSPHORYLATION, GATA3_01, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP

GO Biological Process (11): DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355), signal transduction (GO:0007165), cell differentiation (GO:0030154), positive regulation of peptidyl-serine phosphorylation (GO:0033138), positive regulation of fat cell differentiation (GO:0045600), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of D-glucose import across plasma membrane (GO:0046326), positive regulation of lipid biosynthetic process (GO:0046889), protein stabilization (GO:0050821), regulation of transcription by RNA polymerase II (GO:0006357)

GO Molecular Function (4): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
DNA-templated transcription	2
gene expression	1
RNA biosynthetic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular developmental process	1
positive regulation of protein phosphorylation	1
peptidyl-serine phosphorylation	1
regulation of peptidyl-serine phosphorylation	1
fat cell differentiation	1
positive regulation of cell differentiation	1
regulation of fat cell differentiation	1
positive regulation of RNA biosynthetic process	1
positive regulation of D-glucose transmembrane transport	1
regulation of D-glucose import across plasma membrane	1
D-glucose import across plasma membrane	1
lipid biosynthetic process	1
positive regulation of biosynthetic process	1
positive regulation of lipid metabolic process	1
regulation of lipid biosynthetic process	1
regulation of protein stability	1
transcription by RNA polymerase II	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CREBL2	ETV6	P41212	765
CREBL2	CDKN1B	P46527	588
CREBL2	CREBRF	Q8IUR6	580
CREBL2	GPR19	Q15760	529
CREBL2	MANSC1	Q9H8J5	506
CREBL2	RUSC1	Q9BVN2	456
CREBL2	FOSL2	P15408	444
CREBL2	BORCS5	Q969J3	425
CREBL2	KCNK6	Q9Y257	409
CREBL2	FAM234B	A2RU67	406
CREBL2	DUSP16	Q9BY84	402
CREBL2	CREBZF	Q9NS37	391
CREBL2	FOS	P01100	381
CREBL2	SPRYD3	Q8NCJ5	377
CREBL2	ELF3	P78545	374
CREBL2	ACBD4	Q8NC06	374

IntAct

22 interactions, top by confidence:

A	B	Type	Score
NFE2L2	CREBL2	psi-mi:“MI:0915”(physical association)	0.630
CREBL2	DDIT3	psi-mi:“MI:0915”(physical association)	0.560
CREBL2	PKNOX2	psi-mi:“MI:0915”(physical association)	0.560
CREBL2	CREBRF	psi-mi:“MI:0915”(physical association)	0.560
CREBL2	UBE2I	psi-mi:“MI:0915”(physical association)	0.560
CREBL2	RSL1D1	psi-mi:“MI:0915”(physical association)	0.400
CREBL2	DDIT3	psi-mi:“MI:0915”(physical association)	0.000
CREBL2	CREBRF	psi-mi:“MI:0915”(physical association)	0.000
CREBL2	PKNOX2	psi-mi:“MI:0915”(physical association)	0.000
CREBL2	UBE2I	psi-mi:“MI:0915”(physical association)	0.000
	CREBL2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (13): CREBL2 (Reconstituted Complex), CREBL2 (Two-hybrid), CREBRF (Two-hybrid), PKNOX2 (Two-hybrid), DDIT3 (Two-hybrid), RSL1D1 (Proximity Label-MS), CREBL2 (Affinity Capture-RNA), CREBL2 (Two-hybrid), CREBL2 (Affinity Capture-Western), CREBL2 (FRET), CREBL2 (Affinity Capture-MS), CREBL2 (Affinity Capture-RNA), CREBL2 (Affinity Capture-RNA)

ESM2 similar proteins: A4IGK3, B7ZAP0, O08609, O54941, O55047, O60519, P18847, P26801, P28574, P29596, P37285, P52161, P52162, P52164, P60762, P61244, P61245, P97875, Q07016, Q07866, Q08CW1, Q08DJ0, Q0VCP9, Q0VD32, Q13330, Q28772, Q2KII1, Q32KT0, Q32M00, Q3T0B9, Q56A18, Q5BJU6, Q5R581, Q5ZIL4, Q60765, Q62599, Q642H2, Q6PH81, Q78E65, Q7TMY4

Diamond homologs: A4IGK3, O60519, Q0VD32, Q32M00, Q5BJU6, Q642H2, Q9VL14

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CREBL2	“up-regulates quantity by expression”	PPARG	“transcriptional regulation”
CREBL2	“up-regulates quantity by expression”	CEBPA	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	10
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3065406	NM_001310.4(CREBL2):c.172C>T (p.Arg58Ter)	Likely pathogenic

SpliceAI

734 predictions. Top by Δscore:

Variant	Effect	Δscore
12:12635765:C:CA	acceptor_gain	1.0000
12:12635769:T:TA	acceptor_gain	1.0000
12:12635772:T:A	acceptor_gain	1.0000
12:12612034:G:T	donor_gain	0.9900
12:12613628:G:GT	donor_gain	0.9900
12:12613632:T:TA	donor_gain	0.9900
12:12613633:A:AA	donor_gain	0.9900
12:12613652:G:GT	donor_gain	0.9900
12:12635773:GAA:G	acceptor_loss	0.9900
12:12635775:A:G	acceptor_loss	0.9900
12:12635775:AGGT:A	acceptor_gain	0.9900
12:12635776:GGTG:G	acceptor_gain	0.9900
12:12635975:G:GG	donor_gain	0.9900
12:12635976:T:A	donor_loss	0.9900
12:12637568:A:AG	acceptor_gain	0.9900
12:12637569:G:GG	acceptor_gain	0.9900
12:12637710:TTCCT:T	donor_gain	0.9900
12:12637715:G:GG	donor_gain	0.9900
12:12641988:TTTCA:T	acceptor_loss	0.9900
12:12641989:TTCAG:T	acceptor_loss	0.9900
12:12641990:TCAGG:T	acceptor_loss	0.9900
12:12641991:CAGGG:C	acceptor_loss	0.9900
12:12641992:A:G	acceptor_loss	0.9900
12:12641992:AG:A	acceptor_gain	0.9900
12:12641993:GG:G	acceptor_gain	0.9900
12:12612183:GTAAG:G	donor_gain	0.9800
12:12612186:AGG:A	donor_loss	0.9800
12:12612187:GGT:G	donor_loss	0.9800
12:12612188:G:GG	donor_gain	0.9800
12:12612188:GTA:G	donor_loss	0.9800

AlphaMissense

785 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:12635810:C:A	R17S	1.000
12:12635813:G:C	G18R	1.000
12:12635814:G:A	G18D	1.000
12:12635846:A:G	K29E	1.000
12:12635848:A:C	K29N	1.000
12:12635848:A:T	K29N	1.000
12:12635850:T:A	L30H	1.000
12:12635850:T:C	L30P	1.000
12:12635856:G:C	R32T	1.000
12:12635856:G:T	R32M	1.000
12:12635857:G:C	R32S	1.000
12:12635857:G:T	R32S	1.000
12:12635858:A:C	S33R	1.000
12:12635860:C:A	S33R	1.000
12:12635860:C:G	S33R	1.000
12:12635861:C:G	R34G	1.000
12:12635861:C:T	R34W	1.000
12:12635862:G:C	R34P	1.000
12:12635865:A:C	Q35P	1.000
12:12635866:G:C	Q35H	1.000
12:12635866:G:T	Q35H	1.000
12:12635867:A:C	S36R	1.000
12:12635869:T:A	S36R	1.000
12:12635869:T:G	S36R	1.000
12:12635871:C:A	A37E	1.000
12:12635871:C:T	A37V	1.000
12:12635874:G:C	R38T	1.000
12:12635874:G:T	R38I	1.000
12:12635875:A:C	R38S	1.000
12:12635875:A:T	R38S	1.000

dbSNP variants (sampled 300 via entrez): RS1000077504 (12:12638569 A>G), RS1000108897 (12:12612996 C>T), RS1000142746 (12:12620650 CTTAATCTAAGT>C), RS1000199362 (12:12640225 C>T), RS1000349895 (12:12632158 A>C,G), RS1000387579 (12:12625225 C>T), RS1000459992 (12:12613349 G>A), RS1000712090 (12:12613973 T>C), RS1000738097 (12:12645180 A>G), RS1000818781 (12:12631014 A>G), RS1000939196 (12:12613974 C>T), RS1000978117 (12:12638298 G>A), RS1000996650 (12:12626068 C>A,T), RS1001045021 (12:12625009 C>A,T), RS1001073143 (12:12610048 C>T)

Disease associations

OMIM: gene MIM:603476 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001795_5	Systemic lupus erythematosus	2.000000e-08
GCST003485_3	Response to fenofibrate (HDL cholesterol levels)	9.000000e-06
GCST004286_6	Midgestational circulating levels of PBDEs (fetal genetic effect)	2.000000e-07
GCST008839_219	Height	2.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007805	HDL cholesterol change measurement
EFO:0007959	fetal genotype effect measurement
EFO:0007961	polybrominated biphenyl measurement
EFO:0007962	polybrominated diphenyl ether measurement
EFO:0007964	gestational serum measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
K 7174	increases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	increases expression	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Indomethacin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Mitoxantrone	affects response to substance	1
Testosterone	decreases expression	1
Valproic Acid	decreases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	decreases expression	1
Sodium Selenite	increases expression	1
Particulate Matter	increases abundance, decreases expression	1

Clinical trials (associated diseases)

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