LOCUS       NM_000077                978 bp    mRNA    linear   PRI 03-OCT-2024
DEFINITION  Homo sapiens cyclin dependent kinase inhibitor 2A (CDKN2A),
            transcript variant 1, mRNA.
ACCESSION   NM_000077
VERSION     NM_000077.5
KEYWORDS    RefSeq; MANE Select.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (bases 1 to 978)
  AUTHORS   Kovacs,E., Tompa,P., Liliom,K. and Kalmar,L.
  TITLE     Dual coding in alternative reading frames correlates with intrinsic
            protein disorder
  JOURNAL   Proc Natl Acad Sci U S A 107 (12), 5429-5434 (2010)
   PUBMED   20212158
  REMARK    GeneRIF: Suggests that the long dual coding region and/or the
            resulting disordered protein structure may facilitate NMD escape of
            the variant encoding the p14ARF isoform.
REFERENCE   2  (bases 1 to 978)
  AUTHORS   Irvine,M., Philipsz,S., Frausto,M., Mijatov,B., Gallagher,S.J.,
            Fung,C., Becker,T.M., Kefford,R.F. and Rizos,H.
  TITLE     Amino terminal hydrophobic import signals target the p14(ARF) tumor
            suppressor to the mitochondria
  JOURNAL   Cell Cycle 9 (4), 829-839 (2010)
   PUBMED   20107316
  REMARK    GeneRIF: The interaction of p14(ARF) with mitochondrial proteins,
            including p32 and enables p53-independent cell death.
REFERENCE   3  (bases 1 to 978)
  AUTHORS   Zhang,H.J., Li,W.J., Yang,S.Y., Li,S.Y., Ni,J.H. and Jia,H.T.
  TITLE     8-Chloro-adenosine-induced E2F1 promotes p14ARF gene activation in
            H1299 cells through displacing Sp1 from multiple overlapping
            E2F1/Sp1 sites
  JOURNAL   J Cell Biochem 106 (3), 464-472 (2009)
   PUBMED   19115249
  REMARK    GeneRIF: overlapping E2F1/Sp1 site, being present in multiple
            copies in the p14ARF promoter, may serve as the targets for both
            E2F1 and Sp1, thereby playing a crucial role in response to some
            oncogenic signals and stimulators
REFERENCE   4  (bases 1 to 978)
  AUTHORS   Ivanchuk,S.M., Mondal,S. and Rutka,J.T.
  TITLE     p14ARF interacts with DAXX: effects on HDM2 and p53
  JOURNAL   Cell Cycle 7 (12), 1836-1850 (2008)
   PUBMED   18583933
REFERENCE   5  (bases 1 to 978)
  AUTHORS   Bandyopadhyay,K., Lee,C., Haghighi,A., Baneres,J.L., Parello,J. and
            Gjerset,R.A.
  TITLE     Serine phosphorylation-dependent coregulation of topoisomerase I by
            the p14ARF tumor suppressor
  JOURNAL   Biochemistry 46 (49), 14325-14334 (2007)
   PUBMED   18004878
  REMARK    GeneRIF: ARF is a serine phosphorylation-dependent coregulator of
            topoisomerase I in vivo, and it regulates cellular sensitivity to
            camptothecin by interacting with topoisomerase I.
REFERENCE   6  (bases 1 to 978)
  AUTHORS   Lin,Y.C., Diccianni,M.B., Kim,Y., Lin,H.H., Lee,C.H., Lin,R.J.,
            Joo,S.H., Li,J., Chuang,T.J., Yang,A.S., Kuo,H.H., Tsai,M.D. and
            Yu,A.L.
  TITLE     Human p16gamma, a novel transcriptional variant of p16(INK4A),
            coexpresses with p16(INK4A) in cancer cells and inhibits cell-cycle
            progression
  JOURNAL   Oncogene 26 (49), 7017-7027 (2007)
   PUBMED   17486064
  REMARK    GeneRIF: p16gamma, like p16(INK4A), induced cell-cycle arrest at
            G(0)/G(1), and inhibited cell growth in colony formation assay.
            GeneRIF: p16gamma: a novel transcriptional variant of p16INK4A
REFERENCE   7  (bases 1 to 978)
  AUTHORS   Reef,S., Zalckvar,E., Shifman,O., Bialik,S., Sabanay,H., Oren,M.
            and Kimchi,A.
  TITLE     A short mitochondrial form of p19ARF induces autophagy and
            caspase-independent cell death
  JOURNAL   Mol Cell 22 (4), 463-475 (2006)
   PUBMED   16713577
REFERENCE   8  (bases 1 to 978)
  AUTHORS   Mason,S.L., Loughran,O. and La Thangue,N.B.
  TITLE     p14(ARF) regulates E2F activity
  JOURNAL   Oncogene 21 (27), 4220-4230 (2002)
   PUBMED   12082609
  REMARK    GeneRIF: p14(ARF) down-regulates E2F-dependent transcription. In
            cells undergoing E2F-dependent apoptosis it arrests the cell cycle.
            p14(ARF) has multiple binding domains for E2F-1, one within the
            N-terminal region coinciding with the regulation of E2F activity.
REFERENCE   9  (bases 1 to 978)
  AUTHORS   Hayward,N.
  TITLE     New developments in melanoma genetics
  JOURNAL   Curr Oncol Rep 2 (4), 300-306 (2000)
   PUBMED   11122857
  REMARK    Review article
REFERENCE   10 (bases 1 to 978)
  AUTHORS   Robertson,K.D. and Jones,P.A.
  TITLE     Tissue-specific alternative splicing in the human INK4a/ARF cell
            cycle regulatory locus
  JOURNAL   Oncogene 18 (26), 3810-3820 (1999)
   PUBMED   10445844
REFERENCE   11 (bases 1 to 978)
  AUTHORS   Liu,L., Dilworth,D., Gao,L., Monzon,J., Summers,A., Lassam,N. and
            Hogg,D.
  TITLE     Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon
            and predisposes to melanoma
  JOURNAL   Nat Genet 21 (1), 128-132 (1999)
   PUBMED   9916806
REFERENCE   12 (bases 1 to 978)
  AUTHORS   Stott,F.J., Bates,S., James,M.C., McConnell,B.B., Starborg,M.,
            Brookes,S., Palmero,I., Ryan,K., Hara,E., Vousden,K.H. and
            Peters,G.
  TITLE     The alternative product from the human CDKN2A locus, p14(ARF),
            participates in a regulatory feedback loop with p53 and MDM2
  JOURNAL   EMBO J 17 (17), 5001-5014 (1998)
   PUBMED   9724636
REFERENCE   13 (bases 1 to 978)
  AUTHORS   Hara,E., Smith,R., Parry,D., Tahara,H., Stone,S. and Peters,G.
  TITLE     Regulation of p16CDKN2 expression and its implications for cell
            immortalization and senescence
  JOURNAL   Mol Cell Biol 16 (3), 859-867 (1996)
   PUBMED   8622687
REFERENCE   14 (bases 1 to 978)
  AUTHORS   Mao,L., Merlo,A., Bedi,G., Shapiro,G.I., Edwards,C.D., Rollins,B.J.
            and Sidransky,D.
  TITLE     A novel p16INK4A transcript
  JOURNAL   Cancer Res 55 (14), 2995-2997 (1995)
   PUBMED   7541708
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from BI258230.1, L27211.1,
            BQ012762.1 and BX099567.1.
            
            On May 21, 2020 this sequence version replaced NM_000077.4.
            
            Summary: This gene generates several transcript variants which
            differ in their first exons. At least three alternatively spliced
            variants encoding distinct proteins have been reported, two of
            which encode structurally related isoforms known to function as
            inhibitors of CDK4 kinase. The remaining transcript includes an
            alternate first exon located 20 Kb upstream of the remainder of the
            gene; this transcript contains an alternate open reading frame
            (ARF) that specifies a protein which is structurally unrelated to
            the products of the other variants. This ARF product functions as a
            stabilizer of the tumor suppressor protein p53 as it can interact
            with, and sequester, the E3 ubiquitin-protein ligase MDM2, a
            protein responsible for the degradation of p53. In spite of the
            structural and functional differences, the CDK inhibitor isoforms
            and the ARF product encoded by this gene, through the regulatory
            roles of CDK4 and p53 in cell cycle G1 progression, share a common
            functionality in cell cycle G1 control. This gene is frequently
            mutated or deleted in a wide variety of tumors, and is known to be
            an important tumor suppressor gene. [provided by RefSeq, Sep 2012].
            
            Transcript Variant: This variant (1) is also known as alpha.
            Transcripts 1 and 4, encoding p16INK4a and p14ARF, have distinct
            first exons which contain the translation start codon, and share a
            common second exon, which is translated in different reading
            frames. Thus, the p16INK4a protein encoded by this variant (1)
            lacks sequence similarity to the protein product of variant 4
            (p14ARF).
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            Transcript exon combination :: L27211.1, KC814157.1 [ECO:0000332]
            RNAseq introns              :: single sample supports all introns
                                           SAMEA1968540, SAMEA1968968
                                           [ECO:0000348]
            ##Evidence-Data-END##
            
            ##RefSeq-Attributes-START##
            MANE Ensembl match     :: ENST00000304494.10/ ENSP00000307101.5
            RefSeq Select criteria :: based on manual assertion, conservation,
                                      expression
            ##RefSeq-Attributes-END##
            COMPLETENESS: full length.
PRIMARY     REFSEQ_SPAN         PRIMARY_IDENTIFIER PRIMARY_SPAN        COMP
            1-12                BI258230.1         242-253
            13-662              L27211.1           23-672
            663-737             BQ012762.1         7-81                c
            738-978             BX099567.1         14-254              c
FEATURES             Location/Qualifiers
     source          1..978
                     /organism="Homo sapiens"
                     /mol_type="mRNA"
                     /db_xref="taxon:9606"
                     /chromosome="9"
                     /map="9p21.3"
     gene            1..978
                     /gene="CDKN2A"
                     /gene_synonym="ARF; CAI2; CDK4I; CDKN2; CMM2; INK4; INK4A;
                     MLM; MTS-1; MTS1; P14; P14ARF; P16; P16-INK4A; P16INK4;
                     P16INK4A; P19; P19ARF; TP16"
                     /note="cyclin dependent kinase inhibitor 2A"
                     /db_xref="GeneID:1029"
                     /db_xref="HGNC:HGNC:1787"
                     /db_xref="MIM:600160"
     exon            1..180
                     /gene="CDKN2A"
                     /gene_synonym="ARF; CAI2; CDK4I; CDKN2; CMM2; INK4; INK4A;
                     MLM; MTS-1; MTS1; P14; P14ARF; P16; P16-INK4A; P16INK4;
                     P16INK4A; P19; P19ARF; TP16"
                     /inference="alignment:Splign:2.1.0"
     CDS             31..501
                     /gene="CDKN2A"
                     /gene_synonym="ARF; CAI2; CDK4I; CDKN2; CMM2; INK4; INK4A;
                     MLM; MTS-1; MTS1; P14; P14ARF; P16; P16-INK4A; P16INK4;
                     P16INK4A; P19; P19ARF; TP16"
                     /note="isoform p16INK4a is encoded by transcript variant
                     1; multiple tumor suppressor 1; cell cycle negative
                     regulator beta; CDK4 inhibitor p16-INK4; cyclin-dependent
                     kinase 4 inhibitor A; cyclin-dependent kinase inhibitor 2A
                     (melanoma, p16, inhibits CDK4); alternative reading frame;
                     CDKN2A/ARF Intron 2 lncRNA; multiple tumour suppressor 1;
                     inhibitor of cdk4 A"
                     /codon_start=1
                     /product="cyclin-dependent kinase inhibitor 2A isoform
                     p16INK4a"
                     /protein_id="NP_000068.1"
                     /db_xref="CCDS:CCDS6510.1"
                     /db_xref="GeneID:1029"
                     /db_xref="HGNC:HGNC:1787"
                     /db_xref="MIM:600160"
                     /translation="MEPAAGSSMEPSADWLATAAARGRVEEVRALLEAGALPNAPNSY
                     GRRPIQVMMMGSARVAELLLLHGAEPNCADPATLTRPVHDAAREGFLDTLVVLHRAGA
                     RLDVRDAWGRLPVDLAEELGHRDVARYLRAAAGGTRGSNHARIDAAEGPSDIPD"
     exon            181..487
                     /gene="CDKN2A"
                     /gene_synonym="ARF; CAI2; CDK4I; CDKN2; CMM2; INK4; INK4A;
                     MLM; MTS-1; MTS1; P14; P14ARF; P16; P16-INK4A; P16INK4;
                     P16INK4A; P19; P19ARF; TP16"
                     /inference="alignment:Splign:2.1.0"
     exon            488..978
                     /gene="CDKN2A"
                     /gene_synonym="ARF; CAI2; CDK4I; CDKN2; CMM2; INK4; INK4A;
                     MLM; MTS-1; MTS1; P14; P14ARF; P16; P16-INK4A; P16INK4;
                     P16INK4A; P19; P19ARF; TP16"
                     /inference="alignment:Splign:2.1.0"
     regulatory      715..720
                     /regulatory_class="polyA_signal_sequence"
                     /gene="CDKN2A"
                     /gene_synonym="ARF; CAI2; CDK4I; CDKN2; CMM2; INK4; INK4A;
                     MLM; MTS-1; MTS1; P14; P14ARF; P16; P16-INK4A; P16INK4;
                     P16INK4A; P19; P19ARF; TP16"
                     /note="hexamer: TATAAA"
     polyA_site      737
                     /gene="CDKN2A"
                     /gene_synonym="ARF; CAI2; CDK4I; CDKN2; CMM2; INK4; INK4A;
                     MLM; MTS-1; MTS1; P14; P14ARF; P16; P16-INK4A; P16INK4;
                     P16INK4A; P19; P19ARF; TP16"
                     /note="major polyA site"
     regulatory      945..950
                     /regulatory_class="polyA_signal_sequence"
                     /gene="CDKN2A"
                     /gene_synonym="ARF; CAI2; CDK4I; CDKN2; CMM2; INK4; INK4A;
                     MLM; MTS-1; MTS1; P14; P14ARF; P16; P16-INK4A; P16INK4;
                     P16INK4A; P19; P19ARF; TP16"
                     /note="hexamer: AATAAA"
     polyA_site      978
                     /gene="CDKN2A"
                     /gene_synonym="ARF; CAI2; CDK4I; CDKN2; CMM2; INK4; INK4A;
                     MLM; MTS-1; MTS1; P14; P14ARF; P16; P16-INK4A; P16INK4;
                     P16INK4A; P19; P19ARF; TP16"
ORIGIN      
        1 gagagcaggc agcgggcggc ggggagcagc atggagccgg cggcggggag cagcatggag
       61 ccttcggctg actggctggc cacggccgcg gcccggggtc gggtagagga ggtgcgggcg
      121 ctgctggagg cgggggcgct gcccaacgca ccgaatagtt acggtcggag gccgatccag
      181 gtcatgatga tgggcagcgc ccgagtggcg gagctgctgc tgctccacgg cgcggagccc
      241 aactgcgccg accccgccac tctcacccga cccgtgcacg acgctgcccg ggagggcttc
      301 ctggacacgc tggtggtgct gcaccgggcc ggggcgcggc tggacgtgcg cgatgcctgg
      361 ggccgtctgc ccgtggacct ggctgaggag ctgggccatc gcgatgtcgc acggtacctg
      421 cgcgcggctg cggggggcac cagaggcagt aaccatgccc gcatagatgc cgcggaaggt
      481 ccctcagaca tccccgattg aaagaaccag agaggctctg agaaacctcg ggaaacttag
      541 atcatcagtc accgaaggtc ctacagggcc acaactgccc ccgccacaac ccaccccgct
      601 ttcgtagttt tcatttagaa aatagagctt ttaaaaatgt cctgcctttt aacgtagata
      661 tatgccttcc cccactaccg taaatgtcca tttatatcat tttttatata ttcttataaa
      721 aatgtaaaaa agaaaaacac cgcttctgcc ttttcactgt gttggagttt tctggagtga
      781 gcactcacgc cctaagcgca cattcatgtg ggcatttctt gcgagcctcg cagcctccgg
      841 aagctgtcga cttcatgaca agcattttgt gaactaggga agctcagggg ggttactggc
      901 ttctcttgag tcacactgct agcaaatggc agaaccaaag ctcaaataaa aataaaataa
      961 ttttcattca ttcactca
//
