ARF_MONDO
ID ARF_MONDO Reviewed; 155 AA.
AC O77618;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 1.
DT 03-AUG-2022, entry version 89.
DE RecName: Full=Tumor suppressor ARF {ECO:0000305};
DE AltName: Full=Alternative reading frame;
DE Short=ARF;
DE AltName: Full=Cyclin-dependent kinase inhibitor 2A;
DE AltName: Full=p19ARF;
GN Name=CDKN2A {ECO:0000250|UniProtKB:Q64364};
OS Monodelphis domestica (Gray short-tailed opossum).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Metatheria; Didelphimorphia; Didelphidae; Monodelphis.
OX NCBI_TaxID=13616;
RN [1] {ECO:0000305, ECO:0000312|EMBL:AAC23671.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9839807; DOI=10.1089/dna.1998.17.975;
RA Sherburn T.E., Gale J.M., Ley R.D.;
RT "Cloning and characterization of the CDKN2A and p19ARF genes from
RT Monodelphis domestica.";
RL DNA Cell Biol. 17:975-981(1998).
RN [2] {ECO:0000305, ECO:0000312|EMBL:AAF65223.1}
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND VARIANT LEU-126.
RX PubMed=11398194; DOI=10.1002/mc.1033;
RA Chan J., Robinson E.S., Atencio J., Wang Z., Kazianis S., Coletta L.D.,
RA Nairn R.S., McCarrey J.R.;
RT "Characterization of the CDKN2A and ARF genes in UV-induced melanocytic
RT hyperplasias and melanomas of an opossum (Monodelphis domestica).";
RL Mol. Carcinog. 31:16-26(2001).
CC -!- FUNCTION: Capable of inducing cell cycle arrest in G1 and G2 phases.
CC Acts as a tumor suppressor. Binds to MDM2 and blocks its
CC nucleocytoplasmic shuttling by sequestering it in the nucleolus. This
CC inhibits the oncogenic action of MDM2 by blocking MDM2-induced
CC degradation of p53 and enhancing p53-dependent transactivation and
CC apoptosis. Also induces G2 arrest and apoptosis in a p53-independent
CC manner by preventing the activation of cyclin B1/CDC2 complexes. Binds
CC to BCL6 and down-regulates BCL6-induced transcriptional repression.
CC Binds to E2F1 and MYC and blocks their transcriptional activator
CC activity but has no effect on MYC transcriptional repression. Binds to
CC TOP1/TOPOI and stimulates its activity. This complex binds to rRNA gene
CC promoters and may play a role in rRNA transcription and/or maturation.
CC Interacts with NPM1/B23 and promotes its polyubiquitination and
CC degradation, thus inhibiting rRNA processing. Plays a role in
CC inhibiting ribosome biogenesis, perhaps by binding to the nucleolar
CC localization sequence of transcription termination factor TTF1, and
CC thereby preventing nucleolar localization of TTF1 (By similarity).
CC Interacts with COMMD1 and promotes its 'Lys63'-linked
CC polyubiquitination. Interacts with UBE2I/UBC9 and enhances sumoylation
CC of a number of its binding partners including MDM2 and E2F1. Binds to
CC HUWE1 and represses its ubiquitin ligase activity. May play a role in
CC controlling cell proliferation and apoptosis during mammary gland
CC development (By similarity). {ECO:0000250|UniProtKB:Q64364,
CC ECO:0000250|UniProtKB:Q8N726}.
CC -!- SUBUNIT: Does not interact with cyclins, CDK1, CDK2, CDK4, CDK5 or
CC CDK6. Binds to BCL6, E2F1, HUWE1, MDM2, MYC, NPM1/B23, TOP1/TOPOI and
CC UBE2I/UBC9. Interacts with TBRG1 and COMMD1. Interacts with CDKN2AIP
CC and E4F1. Interacts with CDK5RAP3 and MDM2; form a ternary complex
CC involved in regulation of p53/TP53. Interacts with NOP53; the
CC interaction is direct and promotes ARF nucleoplasmic relocalization and
CC ubiquitin-mediated proteasomal degradation (By similarity). Interacts
CC with TTF1 (via the N-terminal region (NRD) and a C-terminal region);
CC the interaction is direct and inhibits the nucleolar localization of
CC TTF1 (By similarity). {ECO:0000250|UniProtKB:Q64364,
CC ECO:0000250|UniProtKB:Q8N726}.
CC -!- SUBCELLULAR LOCATION: Nucleus, nucleolus
CC {ECO:0000250|UniProtKB:Q8N726}. Nucleus, nucleoplasm
CC {ECO:0000250|UniProtKB:Q8N726}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing, Alternative initiation; Named isoforms=3;
CC Comment=Isoform 1 and isoform tumor suppressor ARF arise due to the
CC use of two alternative first exons joined to a common exon 2 at the
CC same acceptor site but in different reading frames, resulting in two
CC completely different isoforms. {ECO:0000269|PubMed:11398194};
CC Name=tumor suppressor ARF {ECO:0000303|PubMed:11398194};
CC Synonyms=p19ARF {ECO:0000303|PubMed:9839807};
CC IsoId=O77618-1; Sequence=Displayed;
CC Name=1 {ECO:0000303|PubMed:11398194}; Synonyms=CDKN2A
CC {ECO:0000303|PubMed:11398194}, p16INK4a {ECO:0000250|UniProtKB:Q64364};
CC IsoId=O77617-1; Sequence=External;
CC Name=3;
CC IsoId=O77617-2; Sequence=External;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. In the testis, expressed in
CC both somatic and germ cells. Not detected in premeiotic spermatogonia
CC but expressed in both meiotic and postmeiotic cells. In primary tumors,
CC low levels detected in melanocytic hyperplasias. Higher levels found in
CC non-metastatic and metastatic melanomas. {ECO:0000269|PubMed:11398194}.
CC -!- PTM: Ubiquitinated in normal cells by TRIP12 via the ubiquitin fusion
CC degradation (UFD) pathway, a process that mediates ubiquitination at
CC the N-terminus, regardless of the absence of lysine residues.
CC Ubiquitination leads to its proteasomal degradation. In cancer cells,
CC however, TRIP12 is located in a different cell compartment, preventing
CC ubiquitination and degradation. {ECO:0000250|UniProtKB:Q8N726}.
CC -!- CAUTION: The proteins described here are encoded by the gene CDKN2A,
CC but are completely unrelated in terms of sequence and function to
CC cyclin-dependent kinase inhibitor 2A (AC O77617) which is encoded by
CC the same gene. {ECO:0000305}.
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DR EMBL; AF064809; AAC23671.1; -; mRNA.
DR EMBL; AF236862; AAF65223.1; -; mRNA.
DR RefSeq; NP_001028145.1; NM_001032973.1. [O77618-1]
DR AlphaFoldDB; O77618; -.
DR GeneID; 554242; -.
DR KEGG; mdo:554242; -.
DR CTD; 1029; -.
DR Proteomes; UP000002280; Unplaced.
DR GO; GO:0005730; C:nucleolus; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:InterPro.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; ISS:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; IEA:InterPro.
DR GO; GO:0006364; P:rRNA processing; IEA:UniProtKB-KW.
DR InterPro; IPR010868; Tumor_suppres_ARF.
DR Pfam; PF07392; P19Arf_N; 1.
PE 2: Evidence at transcript level;
KW Alternative initiation; Alternative splicing; Apoptosis; Cell cycle;
KW DNA-binding; Nucleus; Reference proteome; rRNA processing; Transcription;
KW Transcription regulation; Tumor suppressor; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1..155
FT /note="Tumor suppressor ARF"
FT /id="PRO_0000144181"
FT REGION 1..59
FT /note="Interaction with CDK5RAP3 and MDM2"
FT /evidence="ECO:0000250|UniProtKB:Q8N726"
FT REGION 55..155
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VARIANT 126
FT /note="P -> L (in some primary melanomas and melanoma cell
FT lines)"
FT /evidence="ECO:0000269|PubMed:11398194"
SQ SEQUENCE 155 AA; 16467 MW; 7FFEEDB931804519 CRC64;
MIRRVRVTVR VSRACRPHHV RIFVAKIVQA LCRASASINQ GTPFQVLLIV RKKRHRGRSG
HDDGQCTPGS NPVAVRGGTQ HPRPDNPHPA SPRRCPGGLP GHSDAAPSGR GAAGCQGLLG
SPACGPRRGT RTPPRGRIPA RGGEGRLNDT VQEAQ
