P51480 (CD2A1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclin-dependent kinase inhibitor 2A, isoforms 1/2

Alternative name(s):
Cyclin-dependent kinase 4 inhibitor A
Short name=CDK4I
p16-INK4a
Short name=p16-INK4

Gene names

Name:	Cdkn2a
Synonyms:	P16ink4a

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	168 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6. This inhibits their ability to interact with cyclins D and to phosphorylate the retinoblastoma protein.
Subunit structure	Heterodimer with CDK4 or CDK6. Predominamt P16 complexes contained CDK6. Interacts with CDK4 (both 'T-172'-phosphorylated and non-phosphorylated forms); the interaction inhibits cyclin D-CDK4 kinase activity. Interacts with ISCO2 By similarity.
Subcellular location	Cytoplasm By similarity. Nucleus By similarity.
Post-translational modification	Phosphorylation seems to increase interaction with CDK4 By similarity.
Polymorphism	Strain BALB/c displays a significantly reduced ability to inhibit phosphorylation of the retinoblastoma protein.
Sequence similarities	Belongs to the CDKN2 cyclin-dependent kinase inhibitor family. Contains 4 ANK repeats.

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Tumor suppressor
Domain	ANK repeat Repeat
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cell aging Inferred from direct assay PubMed 11748239. Source: MGI cell cycle arrest Inferred from direct assay Ref.1. Source: MGI epidermis development Inferred from mutant phenotype PubMed 11551927. Source: MGI negative regulation of cyclin-dependent protein serine/threonine kinase activity Inferred from direct assay PubMed 12130539. Source: MGI negative regulation of mammary gland epithelial cell proliferation Inferred from mutant phenotype PubMed 15105443. Source: MGI positive regulation of apoptotic process involved in mammary gland involution Inferred from mutant phenotype PubMed 15105443. Source: MGI positive regulation of macrophage apoptotic process Inferred from genetic interaction PubMed 20381282. Source: BHF-UCL positive regulation of smooth muscle cell apoptotic process Inferred from genetic interaction PubMed 20381282. Source: BHF-UCL rRNA transcription Inferred from genetic interaction PubMed 18809582. Source: MGI regulation of nucleocytoplasmic transport Inferred from genetic interaction PubMed 15485902. Source: MGI somatic stem cell maintenance Inferred from genetic interaction PubMed 18957199. Source: MGI
Cellular_component	cytoplasm Inferred from direct assay PubMed 12154087. Source: MGI nucleolus Inferred from direct assay PubMed 11718560PubMed 12154087PubMed 15485902PubMed 15567177PubMed 15989966PubMed 16199867. Source: MGI nucleoplasm Inferred from direct assay PubMed 12154087. Source: MGI
Molecular_function	cyclin-dependent protein serine/threonine kinase inhibitor activity Inferred from direct assay PubMed 12130539Ref.1. Source: MGI sequence-specific DNA binding transcription factor activity Inferred from direct assay PubMed 12154087. Source: MGI
Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Note: Isoform 1 and isoform 3 arise due to the use of two alternative first exons joined to a common exon 2 at the same acceptor site but in different reading frames, resulting in two completely different isoforms.

Isoform 1 (identifier: P51480-1)

Also known as: p16INK4a;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P51480-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-43: Missing.

Isoform 3 (identifier: Q64364-1)

Also known as: p19ARF; ARF;

The sequence of this isoform can be found in the external entry Q64364.
Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.

Isoform 4 (identifier: Q64364-2)

Also known as: smARF;

The sequence of this isoform can be found in the external entry Q64364.
Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 168

168

Cyclin-dependent kinase inhibitor 2A, isoforms 1/2

PRO_0000144178

Regions

Repeat

3 – 32

30

ANK 1

Repeat

36 – 64

29

ANK 2

Repeat

69 – 98

30

ANK 3

Repeat

102 – 131

30

ANK 4

Amino acid modifications

Modified residue

152

1

Phosphoserine By similarity

Modified residue

164

1

Phosphoserine By similarity

Natural variations

Alternative sequence

1 – 43

43

Missing in isoform 2.

VSP_015867

Natural variant

12

1

A → V in some liver tumors. Ref.9

Natural variant

18

1

H → P in strain: 020, BALB/c, BALB/cJ, C3H/21BG, C3H/HeJ, CBA/J, MA/M4J and PL/J. Ref.2 Ref.7 Ref.8

Natural variant

27

1

G → E in some liver tumors. Ref.9

Natural variant

51

1

V → I in strain: BALB/c and BALB/cJ. Ref.2 Ref.7

Natural variant

73

1

P → L in some liver tumors. Ref.9

Natural variant

74

1

V → M in plasmacytoma cell lines. Ref.2

Natural variant

75

1

H → Y in plasmacytoma cell lines. Ref.2

Natural variant

90

1

H → Q in strain: BALB/cJ, C57BL/6J and MOLF/Ei. Ref.7

Natural variant

90

1

H → R in plasmacytoma cell lines. Ref.2

Natural variant

127

1

C → S in strain: BALB/cJ, C57BL/6J and MOLF/Ei. Ref.7

Experimental info

Mutagenesis

64

1

C → G or R: No effect on activity. Ref.10

Mutagenesis

76

1

D → N: Loss of activity. Ref.10

Mutagenesis

84 – 85

2

Missing: Loss of activity.

Sequence conflict

11

1

Missing in AAA85453. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

168

Helix Strand Turn

Details...

Turn

13 – 15

3

Helix

17 – 25

9

Helix

40 – 43

4

Helix

49 – 58

10

Helix

72 – 80

9

Helix

83 – 91

9

Helix

106 – 113

8

Helix

116 – 123

8

Turn

124 – 126

3

Helix

139 – 145

7

Helix

149 – 157

9

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (p16INK4a) [UniParc]. Last modified October 25, 2005. Version 2. Checksum: 9A6B0F24F34D5FEC	FASTA	168	17,941
	10 20 30 40 50 60 MESAADRLAR AAAQGRVHDV RALLEAGVSP NAPNSFGRTP IQVMMMGNVH VAALLLNYGA 70 80 90 100 110 120 DSNCEDPTTF SRPVHDAARE GFLDTLVVLH GSGARLDVRD AWGRLPLDLA QERGHQDIVR 130 140 150 160 YLRSAGCSLC SAGWSLCTAG NVAQTDGHSF SSSTPRALEL RGQSQEQS
	Isoform 2 [UniParc]. Checksum: 97BE6143D7C8542D	FASTA	125	13,458
	10 20 30 40 50 60 MMMGNVHVAA LLLNYGADSN CEDPTTFSRP VHDAAREGFL DTLVVLHGSG ARLDVRDAWG 70 80 90 100 110 120 RLPLDLAQER GHQDIVRYLR SAGCSLCSAG WSLCTAGNVA QTDGHSFSSS TPRALELRGQ SQEQS
	Isoform 3 (p19ARF) (ARF) [UniParc]. See Q64364.		–	–
	Isoform 4 (smARF) [UniParc]. See Q64364.		–	–

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of murine p16INK4a and p15INK4b genes." Quelle D.E., Ashmun R.A., Hannon G.J., Rehberger P.A., Trono D., Richter K.H., Walker C., Beach D., Sherr C.J., Serrano M. Oncogene 11:635-645(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Cdkn2a, the cyclin-dependent kinase inhibitor encoding p16(INK4a) and p19(ARF), is a candidate for the plasmacytoma susceptibility locus, Pctr1." Zhang S., Ramsay E.S., Mock B.A. Proc. Natl. Acad. Sci. U.S.A. 95:2429-2434(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS PRO-18; ILE-51; MET-74; TYR-75 AND ARG-90. Strain: BALB/c and DBA/2N. Tissue: Spleen.
[3]	"Cloning and structure analysis of murine p16INK4a." Gong Z., Li J., Fu J. Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: 129/SvJ.
[4]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[5]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6J.
[6]	"Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas." Malumbres M., de Castro I.P., Santos J., Melendez B., Mangues R., Serrano M., Pellicer A., Fernandez-Piqueras J. Oncogene 14:1361-1370(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-155. Strain: C57BL/6J X DBA.
[7]	"Comparative analysis of the p16(INK4a) and p15(INK4b) DNA sequences in mouse inbred strains." Santos J., Melendez B., Perez de Castro I., Malumbres M., Serrano M., Pellicer A., Fernandez-Piqueras J. Submitted (OCT-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-155, VARIANTS PRO-18; ILE-51; GLN-90 AND SER-127. Strain: BALB/cJ, C57BL/6J, CAST/Ei, MOLF/Ei and RF/J.
[8]	"Sequence variation and chromosomal mapping of the murine Cdkn2a tumor suppressor gene." Herzog C.R., You M. Mamm. Genome 8:65-66(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-42 (ISOFORM 1), VARIANT PRO-18. Strain: 020, 129/J, A/J, A/Wy, AKR/J, B10.A, B10.D2(58N), BALB/c, C3H/21BG, C3H/HeJ, C57BL/10SCN, C57BL/10SN, C57BL/6By, C57BL/6J, C57BR/cdJ, CBA/J, DBA/2J, HS/IBG, LP/J, LS/IBG, MA/M4J, PL/J, RF/J, Sencar, SJL/J, SM/J, ST/J and SWR/J. Tissue: Lung.
[9]	"Induction of mutations in Ki-ras and INK4a in liver tumors of mice exposed in utero to 3-methylcholanthrene." Gressani K.M., Rollins L.A., Leone-Kabler S., Cline J.M., Miller M.S. Carcinogenesis 19:1045-1052(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-42, VARIANTS VAL-12; GLU-27 AND LEU-73.
[10]	"Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF." Quelle D.E., Cheng M., Ashmun R.A., Sherr C.J. Proc. Natl. Acad. Sci. U.S.A. 94:669-673(1997) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF CYS-64; ASP-76 AND 84-ASP-THR-85.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L76150 mRNA. Translation: AAA85453.1.
AF044335 mRNA. Translation: AAC08962.1.
AF044336 mRNA. Translation: AAC08963.1.
AF332190 Genomic DNA. Translation: AAK83159.1.
AK155307 mRNA. Translation: BAE33180.1.
AL831719 Genomic DNA. Translation: CAM16002.1.
AL831719 Genomic DNA. Translation: CAM16003.1.
U66087, U66086 Genomic DNA. Translation: AAB39600.1.
U79625 Genomic DNA. Translation: AAD00223.1.
U79626 Genomic DNA. Translation: AAD00224.1.
U79627 Genomic DNA. Translation: AAD00225.1.
U79628 Genomic DNA. Translation: AAD00226.1.
U79630 Genomic DNA. Translation: AAD00227.1.
U79631 Genomic DNA. Translation: AAD00228.1.
U79632 Genomic DNA. Translation: AAD00229.1.
U49279 Genomic DNA. Translation: AAC00051.1.
U49280 Genomic DNA. Translation: AAC00052.1.
AF004588 Genomic DNA. Translation: AAB61416.1.

IPI

IPI00122635.
IPI00283736.

RefSeq

NP_001035744.1. NM_001040654.1.

UniGene

Mm.4733.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1LNN	model	-	A	12-159	[»]

ProteinModelPortal

P51480.

SMR

P51480. Positions 2-126.

ModBase

Search...

PTM databases

PhosphoSite

P51480.

Proteomic databases

PRIDE

P51480.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000060501; ENSMUSP00000061847; ENSMUSG00000044303.
ENSMUST00000107131; ENSMUSP00000102748; ENSMUSG00000044303.

GeneID

12578.

KEGG

mmu:12578.

UCSC

uc008toh.1. mouse.

Organism-specific databases

CTD

1029.

MGI

MGI:104738. Cdkn2a.

Phylogenomic databases

eggNOG

NOG42176.

GeneTree

ENSGT00390000008249.

HOVERGEN

HBG050870.

KO

K06621.

OrthoDB

EOG49KFS3.

Gene expression databases

ArrayExpress

P51480.

Bgee

P51480.

CleanEx

MM_CDKN2A.

Genevestigator

P51480.

GermOnline

ENSMUSG00000044303. Mus musculus.

Family and domain databases

Gene3D

1.25.40.20. 1 hit.

InterPro

IPR002110. Ankyrin_rpt.
IPR020683. Ankyrin_rpt-contain_dom.
[Graphical view]

Pfam

PF00023. Ank. 1 hit.
PF12796. Ank_2. 1 hit.
[Graphical view]

SMART

SM00248. ANK. 4 hits.
[Graphical view]

SUPFAM

SSF48403. ANK. 1 hit.

PROSITE

PS50297. ANK_REP_REGION. 1 hit.
PS50088. ANK_REPEAT. False negative.
[Graphical view]

ProtoNet

Search...

Other

NextBio

281698.

SOURCE

Search...

Entry information

Entry name

CD2A1_MOUSE

Accession

Primary (citable) accession number: P51480
Secondary accession number(s): A2ANM1 , A2ANM2, O89088, P97510, P97937, Q6PEA2, Q78E39, Q78E57, Q792X7, Q9QWH6, Q9QWH7, Q9QWH8

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 25, 2005
Last modified:	May 1, 2013
This is version 115 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program