Reviewed, UniProtKB/Swiss-Prot P38936 (CDN1A_HUMAN)

Names and origin

Protein names

Recommended name:
    Cyclin-dependent kinase inhibitor 1
Alternative name(s):
    p21
    CDK-interacting protein 1
    Melanoma differentiation-associated protein 6
      Short name=MDA-6

Gene names

Name:	CDKN1A
Synonyms:	CAP20, CDKN1, CIP1, MDA6, PIC1, SDI1, WAF1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	164 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	May be the important intermediate by which p53 mediates its role as an inhibitor of cellular proliferation in response to DNA damage. Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression.
Subcellular location	Cytoplasm. Nucleus. Ref.13
Tissue specificity	Expressed in all adult human tissues, with 5-fold lower levels observed in the brain.
Induction	By p53, mezerein (antileukemic compound) and interferon beta.
Post-translational modification	Phosphorylation of Thr-145 by Akt or of Ser-146 by PKC impairs binding to PCNA.
Sequence similarities	Belongs to the CDI family.

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Domain	Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Protein kinase inhibitor
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	G1/S transition of mitotic cell cycle Inferred from direct assay. Source: UniProtKB G2/M transition of mitotic cell cycle Inferred from mutant phenotype. Source: UniProtKB cell cycle arrest Inferred from mutant phenotype. Source: UniProtKB cellular response to extracellular stimulus Inferred from mutant phenotype. Source: UniProtKB induction of apoptosis by intracellular signals Traceable author statement. Source: ProtInc negative regulation of cell growth Inferred from direct assay. Source: UniProtKB negative regulation of cell proliferation Inferred from direct assay. Source: UniProtKB negative regulation of phosphorylation Inferred from direct assay. Source: UniProtKB positive regulation of fibroblast proliferation Inferred from mutant phenotype. Source: UniProtKB
Cellular component	cyclin-dependent protein kinase holoenzyme complex Inferred from direct assay. Source: UniProtKB cytosol Inferred from Experiment. Source: Reactome nucleoplasm Inferred from Experiment. Source: Reactome
Molecular function	cyclin-dependent protein kinase inhibitor activity Ref.1 Inferred from Experiment. Source: Reactome zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CCNA1	P78396	1	EBI-375077,EBI-375065
CCNA2	P20248	1	EBI-375077,EBI-457097
CCNB2	O95067	1	EBI-375077,EBI-375024
CCND1	P24385	2	EBI-375077,EBI-375001
CCND3	P30281	1	EBI-375077,EBI-375013
CCNE1	P24864	3	EBI-375077,EBI-519526
CCNE2	O96020	1	EBI-375077,EBI-375033
CDC45L	O75419	1	EBI-375077,EBI-374969
CDC5L	Q99459	1	EBI-375077,EBI-374880
CDC6	Q99741	1	EBI-375077,EBI-374862
CDC7	O00311	1	EBI-375077,EBI-374980
CDK2	P24941	5	EBI-375077,EBI-375096
CDK4	P11802	2	EBI-375077,EBI-295644
CDK5	Q00535	1	EBI-375077,EBI-1041567
CDK6	Q00534	1	EBI-375077,EBI-295663
GMNN	O75496	1	EBI-375077,EBI-371669
MCM10	Q7L590	1	EBI-375077,EBI-374912
pcn1	Q03392	1	EBI-375077,EBI-768724	From a different organism.
PCNA	P12004	1	EBI-375077,EBI-358311
PFTK1	O94921	4	EBI-375077,EBI-1043945

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.11

Chain

2 – 164

163

Cyclin-dependent kinase inhibitor 1

PRO_0000190079

Regions

Zinc finger

13 – 41

29

C4-type Potential

Motif

141 – 156

16

Nuclear localization signal Potential

Amino acid modifications

Modified residue

2

1

N-acetylserine Ref.11

Modified residue

130

1

Phosphoserine Ref.14 Ref.15

Modified residue

145

1

Phosphothreonine; by PKA and PKB/AKT1 Ref.13 Ref.12

Modified residue

146

1

Phosphoserine; by PKC Ref.12

Modified residue

160

1

Phosphoserine; by PKC; in vitro Ref.12

Natural variations

Natural variant

4

1

P → L: dbSNP rs4986866.

VAR_048686

Natural variant

31

1

S → R: dbSNP rs1801270. Ref.7 Ref.8 Ref.10

VAR_011870

Natural variant

63

1

F → L: dbSNP rs4986867.

VAR_048687

Natural variant

149

1

D → G: dbSNP rs1801724.

VAR_014875

Experimental info

Mutagenesis

145

1

T → A: Reduces phosphorylation by Akt; no change in interaction with PCNA, CDK2 or CDK4; no change in subcellular location. Ref.13

Mutagenesis

145

1

T → D: No interaction with PCNA; 59% inhibition of CDK2 binding; modest inhibition of CDK4 binding; no change in subcellular location. Ref.13

Mutagenesis

146

1

S → A: No change in interaction with PCNA. Ref.13

Mutagenesis

146

1

S → D: Reduces interaction with PCNA. Ref.13

Secondary structure

1

.

.

.

.

.

164

Helix Strand Turn

Details...

Helix

147 – 149

3

Beta strand

151 – 158

8

Sequences

	Sequence		Length	Mass (Da)
	P38936-1 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 98D1E7C519ADFCA9	FASTA	164	18,119
	10 20 30 40 50 60 MSEPAGDVRQ NPCGSKACRR LFGPVDSEQL SRDCDALMAG CIQEARERWN FDFVTETPLE 70 80 90 100 110 120 GDFAWERVRG LGLPKLYLPT GPRRGRDELG GGRRPGTSPA LLQGTAEEDH VDLSLSCTLV 130 140 150 160 PRSGEQAEGS PGGPGDSQGR KRRQTSMTDF YHSKRRLIFS KRKP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases." Harper J.W., Adami G.R., Wei N., Keyomarsi K., Elledge S.J. Cell 75:805-816(1993) [PubMed: 8242751] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"WAF1, a potential mediator of p53 tumor suppression." El-Deiry W.S., Tokino T., Velculescu V.E., Levy D.B., Parsons R., Trent J.M., Lin D., Mercer W.E., Kinzler K.W., Vogelstein B. Cell 75:817-825(1993) [PubMed: 8242752] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"p21 is a universal inhibitor of cyclin kinases." Xiong Y., Hannon G.J., Zhang H., Casso D., Kobayashi R., Beach D. Nature 366:701-704(1993) [PubMed: 8259214] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"Use of a sensitive and efficient subtraction hybridization protocol for the identification of genes differentially regulated during the induction of differentiation in human melanoma cells." Jiang H., Fisher P.B. Mol. Cell. Differ. 1:285-299(1993) Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	"The melanoma differentiation-associated gene mda-6, which encodes the cyclin-dependent kinase inhibitor p21, is differentially expressed during growth, differentiation and progression in human melanoma cells." Jiang H., Lin J., Su Z.Z., Herlyn M., Kerbel R.S., Weissman B.E., Welch D.R., Fisher P.B. Oncogene 10:1855-1864(1995) [PubMed: 7753561] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[6]	"Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen." Noda A., Ning Y., Venable S.F., Pereira-Smith O.M., Smith J.R. Exp. Cell Res. 211:90-98(1994) [PubMed: 8125163] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[7]	"Two variants of the CIP1/WAF1 gene occur together and are associated with human cancer." Mousses S., Oezcelik H., Lee P.D., Malkin D., Bull S.B., Andrulis I.L. Hum. Mol. Genet. 4:1089-1092(1995) [PubMed: 7655464] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT ARG-31.
[8]	NIEHS SNPs program Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT ARG-31.
[9]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed: 14574404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[10]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ARG-31. Tissue: Eye and Lung.
[11]	"N-acetylation and ubiquitin-independent proteasomal degradation of p21(Cip1)." Chen X., Chi Y., Bloecher A., Aebersold R., Clurman B.E., Roberts J.M. Mol. Cell 16:839-847(2004) [PubMed: 15574338] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-16, ACETYLATION AT SER-2.
[12]	"Reversible phosphorylation at the C-terminal regulatory domain of p21(Waf1/Cip1) modulates proliferating cell nuclear antigen binding." Scott M.T., Morrice N., Ball K.L. J. Biol. Chem. 275:11529-11537(2000) [PubMed: 10753973] [Abstract] Cited for: PROTEIN SEQUENCE OF 136-148, PHOSPHORYLATION AT THR-145; SER-146 AND SER-160, MASS SPECTROMETRY.
[13]	"Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells." Roessig L., Jadidi A.S., Urbich C., Badorff C., Zeiher A.M., Dimmeler S. Mol. Cell. Biol. 21:5644-5657(2001) [PubMed: 11463845] [Abstract] Cited for: PHOSPHORYLATION AT THR-145, MUTAGENESIS OF THR-145 AND SER-146, SUBCELLULAR LOCATION.
[14]	"A probability-based approach for high-throughput protein phosphorylation analysis and site localization." Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P. Nat. Biotechnol. 24:1285-1292(2006) [PubMed: 16964243] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-130, MASS SPECTROMETRY. Tissue: Epithelium.
[15]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-130, MASS SPECTROMETRY.
[16]	"Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA." Gulbis J.M., Kelman Z., Hurwitz J., O'Donnell M., Kuriyan J. Cell 87:297-306(1996) [PubMed: 8861913] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 139-160.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

NIEHS-SNPs

Cross-references

Sequence databases

EMBLGenBankDDBJ

L25610 mRNA. Translation: AAA16109.1.
S67388 mRNA. Translation: AAB29246.1.
U09579 mRNA. Translation: AAA85641.1.
U03106 mRNA. Translation: AAC04313.1.
L26165 mRNA. Translation: AAA19811.1.
L47232 mRNA. Translation: AAB59559.1. Different initiation.
L47233 mRNA. Translation: AAB59560.1. Different initiation.
AF497972 Genomic DNA. Translation: AAM11787.1.
Z85996 Genomic DNA. Translation: CAB06656.1.
BC000275 mRNA. Translation: AAH00275.1.
BC000312 mRNA. Translation: AAH00312.1.
BC001935 mRNA. Translation: AAH01935.1.
BC013967 mRNA. Translation: AAH13967.1.

IPI

IPI00009384.

PIR

I54380.
I68674.

RefSeq

NP_000380.1.
NP_510867.1.

UniGene

Hs.370771

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1AXC	X-ray	2.60	B/D/F	139-160	[»]

DisProt

DP00016.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:246N.

IntAct

P38936. 33 interactions.

PTM databases

PhosphoSite

P38936.

2-D gel databases

SWISS-2DPAGE

P38936.

Proteomic databases

PRIDE

P38936.

Genome annotation databases

Ensembl

ENSG00000124762. Homo sapiens. [Contig view]

GeneID

1026.

KEGG

hsa:1026.

Organism-specific databases

GeneCards

GC06P036754.

H-InvDB

HIX0005824.

HGNC

HGNC:1784. CDKN1A.

HPA

CAB000064.

MIM

116899. gene.

PharmGKB

PA104.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

P38936.

OMA

P38936. RRDCDAL.

Enzyme and pathway databases

Pathway_Interaction_DB

angiopoietinreceptor_pathway. Angiopoietin receptor Tie2-mediated signaling.
pi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.
hdac_classiii_pathway. Signaling events mediated by HDAC Class III.
prlsignalingeventspathway. Signaling events mediated by PRL.

Reactome

REACT_152. Cell Cycle, Mitotic.
REACT_1538. Cell Cycle Checkpoints.
REACT_383. DNA Replication.

Gene expression databases

ArrayExpress

P38936.

Bgee

P38936.

CleanEx

HS_CDKN1A.

GermOnline

ENSG00000124762. Homo sapiens.

Family and domain databases

InterPro

IPR003175. CDI.
[Graphical view]

PANTHER

PTHR10265. CDI. 1 hit.

Pfam

PF02234. CDI. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

4309.

SOURCE

Search...

Entry information

Entry name

CDN1A_HUMAN

Accession

Primary (citable) accession number: P38936
Secondary accession number(s): Q14010, Q9BUT4

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	January 23, 2007
Last modified:	June 16, 2009
This is version 108 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)