P39689 (CDN1A_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclin-dependent kinase inhibitor 1

Alternative name(s):
CDK-interacting protein 1
Melanoma differentiation-associated protein
p21

Gene names

Name:	Cdkn1a
Synonyms:	Cip1, Waf1

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	159 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/TP53 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. 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 By similarity.
Subunit structure	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 By similarity. 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 PIM1 By similarity. Ref.5
Subcellular location	Cytoplasm By similarity. Nucleus Ref.5.
Induction	By p53, mezerein (antileukemic compound) and interferon beta.
Domain	The C-terminal is required for nuclear localization of the cyclin D-CDK4 complex By similarity. The PIP-box K+4 motif mediates both the interaction with PCNA and the recuitment 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 By similarity.
Post-translational modification	Phosphorylation of Thr-140 or Ser-141 impairs binding to PCNA. Phosphorylation at Ser-112 by GSK3-beta enhances ubiquitination by the DCX(DTL) complex By similarity. Phosphorylation of Thr-140 by PIM2 enhances its stability and inhibits cell proliferation. Phosphorylation of Thr-140 by PIM1 results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. 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 By similarity. Acetylation leads to protein stability. Acetylated in vitro on Lys-136, Lys-149, Lys-156 and Lys-158. Deacetylation by HDAC1 is prevented by competitive binding of C10orf90/FATS to HDAC1.
Sequence similarities	Belongs to the CDI family.

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Cytoplasm Nucleus
Domain	Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Protein kinase inhibitor
PTM	Acetylation Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest Inferred from electronic annotation. Source: Compara G1/S transition of mitotic cell cycle Inferred from electronic annotation. Source: Compara G2/M transition of mitotic cell cycle Inferred from electronic annotation. Source: Compara Ras protein signal transduction Inferred from electronic annotation. Source: Compara cellular response to extracellular stimulus Inferred from electronic annotation. Source: Compara cellular response to ionizing radiation Inferred from electronic annotation. Source: Compara cellular senescence Inferred from electronic annotation. Source: Compara mitotic cell cycle arrest Inferred from direct assay PubMed 17515607. Source: MGI negative regulation of apoptotic process Inferred from mutant phenotype PubMed 12952892. Source: MGI negative regulation of cell growth Inferred from electronic annotation. Source: Compara negative regulation of cell proliferation Inferred from mutant phenotype PubMed 12759355PubMed 14712235. Source: MGI negative regulation of cyclin-dependent protein serine/threonine kinase activity Inferred from direct assay PubMed 12130539. Source: MGI negative regulation of gene expression Inferred from mutant phenotype PubMed 11981756. Source: MGI organ regeneration Inferred from electronic annotation. Source: Compara positive regulation of B cell proliferation Inferred from genetic interaction PubMed 12970760. Source: MGI positive regulation of fibroblast proliferation Inferred from electronic annotation. Source: Compara positive regulation of programmed cell death Inferred from mutant phenotype PubMed 12759355. Source: MGI positive regulation of reactive oxygen species metabolic process Inferred from electronic annotation. Source: Compara regulation of DNA biosynthetic process Inferred from mutant phenotype PubMed 11981756. Source: MGI regulation of mitotic cell cycle Inferred from mutant phenotype PubMed 11981756. Source: MGI regulation of protein import into nucleus, translocation Inferred from mutant phenotype PubMed 11981756. Source: MGI response to DNA damage stimulus Inferred from mutant phenotype PubMed 12952892. Source: MGI response to UV Inferred from mutant phenotype PubMed 12952892. Source: MGI response to arsenic-containing substance Inferred from electronic annotation. Source: Compara response to corticosterone stimulus Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara response to hyperoxia Inferred from electronic annotation. Source: Compara response to organic nitrogen Inferred from electronic annotation. Source: Compara response to toxin Inferred from electronic annotation. Source: Compara
Cellular_component	PCNA-p21 complex Inferred from sequence or structural similarity. Source: UniProtKB cyclin-dependent protein kinase holoenzyme complex Inferred from physical interaction PubMed 12970760. Source: MGI cytosol Inferred from direct assay PubMed 15964824. Source: MGI
Molecular_function	cyclin binding Inferred from direct assay PubMed 12124778. Source: MGI cyclin-dependent protein kinase activating kinase activity Inferred from electronic annotation. Source: Compara cyclin-dependent protein serine/threonine kinase inhibitor activity Inferred from direct assay PubMed 12130539. Source: MGI metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Gadd45g	Q9Z111	2	EBI-1174103,EBI-1173616

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed By similarity
	Chain	2 – 159	158	Cyclin-dependent kinase inhibitor 1		PRO_0000190080
Regions
	Zinc finger	12 – 40	29	C4-type Potential
	Region	17 – 24	8	Required for binding cyclins By similarity
	Region	53 – 58	6	Required for binding CDKs By similarity
	Motif	135 – 159	25	PIP-box K+4 motif
Amino acid modifications
	Modified residue	2	1	N-acetylserine By similarity
	Modified residue	112	1	Phosphoserine; by GSK3-beta By similarity
	Modified residue	125	1	Phosphoserine By similarity
	Modified residue	140	1	Phosphothreonine; by PKA; PKB/AKT1; PIM1 and PIM2 By similarity
	Modified residue	141	1	Phosphoserine By similarity
Experimental info
	Sequence conflict	30	1	R → S no nucleotide entry Ref.4
	Sequence conflict	56 – 57	2	TP → RQ no nucleotide entry Ref.4

Sequences

	Sequence		Length	Mass (Da)
	P39689 [UniParc]. Last modified January 23, 2007. Version 4. Checksum: 37B7C22B9A2FD089	FASTA	159	17,785
	10 20 30 40 50 60 MSNPGDVRPV PHRSKVCRCL FGPVDSEQLR RDCDALMAGC LQEARERWNF DFVTETPLEG 70 80 90 100 110 120 NFVWERVRSL GLPKVYLSPG SRSRDDLGGD KRPSTSSALL QGPAPEDHVA LSLSCTLVSE 130 140 150 RPEDSPGGPG TSQGRKRRQT SLTDFYHSKR RLVFCKRKP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning, sequencing, chromosomal localization and expression of mouse p21 (Waf1)." Huppi K., Siwarski D., Dosik J., Michieli P., Chedid M., Reed S., Mock B., Givol D., Mushinski J.F. Oncogene 9:3017-3020(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: BXSB. Tissue: Spleen.
[2]	"Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues." El-Deiry W.S., Tokino T., Waldman T., Velculescu V.E., Oliner J.D., Burell M., Hill D.E., Rees J.L., Hamilton S.R., Kinzler K.W., Vogelstein B. Cancer Res. 55:2910-2919(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J. Tissue: Mammary gland.
[4]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-143.
[5]	"An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis." Li Z., Zhang Q., Mao J.H., Weise A., Mrasek K., Fan X., Zhang X., Liehr T., Lu K.H., Balmain A., Cai W.W. Oncogene 29:2659-2671(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HDAC1, SUBCELLULAR LOCATION, ACETYLATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U09507 mRNA. Translation: AAB60456.1. U24173 mRNA. Translation: AAC52220.1. BC002043 mRNA. Translation: AAH02043.1.
IPI	IPI00108058.
PIR	A49438. I49023.
RefSeq	NP_001104569.1. NM_001111099.1. NP_031695.1. NM_007669.4.
UniGene	Mm.195663.
3D structure databases
ProteinModelPortal	P39689.
SMR	P39689. Positions 13-79.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-24178N.
IntAct	P39689. 2 interactions.
PTM databases
PhosphoSite	P39689.
Proteomic databases
PRIDE	P39689.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000023829; ENSMUSP00000023829; ENSMUSG00000023067. ENSMUST00000119901; ENSMUSP00000113150; ENSMUSG00000023067. ENSMUST00000122348; ENSMUSP00000112411; ENSMUSG00000023067.
GeneID	12575.
KEGG	mmu:12575.
Organism-specific databases
CTD	1026.
MGI	MGI:104556. Cdkn1a.
Phylogenomic databases
eggNOG	NOG290902.
HOGENOM	HOG000285999.
HOVERGEN	HBG050868.
InParanoid	P39689.
KO	K06625.
OMA	RRDCDAL.
OrthoDB	EOG437RG1.
Gene expression databases
ArrayExpress	P39689.
Bgee	P39689.
CleanEx	MM_CDKN1A.
Genevestigator	P39689.
GermOnline	ENSMUSG00000023067. Mus musculus.
Family and domain databases
InterPro	IPR003175. CDI. [Graphical view]
PANTHER	PTHR10265. PTHR10265. 1 hit.
Pfam	PF02234. CDI. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	CDKN1A. mouse.
NextBio	281686.
SOURCE	Search...

Entry information

Entry name

CDN1A_MOUSE

Accession

Primary (citable) accession number: P39689

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 111 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program