ARF_RAT
ID ARF_RAT Reviewed; 160 AA.
AC Q8QZZ9;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2002, sequence version 1.
DT 03-AUG-2022, entry version 101.
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:0000312|EMBL:AAL76336.1, ECO:0000312|RGD:2323};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1] {ECO:0000305, ECO:0000312|EMBL:AAL76336.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=ACI/SegHsd {ECO:0000312|EMBL:AAL76336.1},
RC Brown Norway/SsNHsd {ECO:0000312|EMBL:AAT92509.1}, and
RC COP {ECO:0000312|EMBL:AAL76337.1};
RC TISSUE=Lung {ECO:0000312|EMBL:AAL76336.1};
RA Buckles L.K., Shull J.D.;
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [2] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-63, AND TISSUE SPECIFICITY.
RC STRAIN=Fischer 344/N;
RX PubMed=9032263; DOI=10.1128/mcb.17.3.1366;
RA Swafford D.S., Middleton S.K., Palmisano W.A., Nikula K.J., Tesfaigzi J.,
RA Baylin S.B., Herman J.G., Belinsky S.A.;
RT "Frequent aberrant methylation of p16INK4a in primary rat lung tumors.";
RL Mol. Cell. Biol. 17:1366-1374(1997).
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; Named isoforms=2;
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:0000250|UniProtKB:Q64363};
CC Name=tumor suppressor ARF {ECO:0000250|UniProtKB:Q64363};
CC Synonyms=p19ARF;
CC IsoId=Q8QZZ9-1; Sequence=Displayed;
CC Name=1 {ECO:0000250|UniProtKB:Q8N726}; Synonyms=p16INK4a
CC {ECO:0000250|UniProtKB:Q8N726};
CC IsoId=Q9R0Z3-1; Sequence=External;
CC -!- TISSUE SPECIFICITY: Widely expressed with very low levels in kidney and
CC colon. {ECO:0000269|PubMed:9032263}.
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 Q9R0Z3) which is encoded by
CC the same gene. {ECO:0000305}.
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DR EMBL; AF474974; AAL76336.1; -; mRNA.
DR EMBL; AF474975; AAL76337.1; -; mRNA.
DR EMBL; AY679727; AAT92509.1; -; mRNA.
DR EMBL; L81168; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR AlphaFoldDB; Q8QZZ9; -.
DR iPTMnet; Q8QZZ9; -.
DR PhosphoSitePlus; Q8QZZ9; -.
DR UCSC; RGD:2323; rat. [Q8QZZ9-1]
DR RGD; 2323; Cdkn2a.
DR InParanoid; Q8QZZ9; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0001652; C:granular component; ISO:RGD.
DR GO; GO:0005730; C:nucleolus; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0032991; C:protein-containing complex; ISO:RGD.
DR GO; GO:0035985; C:senescence-associated heterochromatin focus; ISO:RGD.
DR GO; GO:0004861; F:cyclin-dependent protein serine/threonine kinase inhibitor activity; ISO:RGD.
DR GO; GO:0097718; F:disordered domain specific binding; ISO:RGD.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0097371; F:MDM2/MDM4 family protein binding; ISO:RGD.
DR GO; GO:0051059; F:NF-kappaB binding; ISO:RGD.
DR GO; GO:0019901; F:protein kinase binding; ISO:RGD.
DR GO; GO:0047485; F:protein N-terminus binding; ISO:RGD.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:RGD.
DR GO; GO:0019789; F:SUMO transferase activity; ISO:RGD.
DR GO; GO:1990948; F:ubiquitin ligase inhibitor activity; ISO:RGD.
DR GO; GO:0055105; F:ubiquitin-protein transferase inhibitor activity; ISO:RGD.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:RGD.
DR GO; GO:0007568; P:aging; IEP:RGD.
DR GO; GO:1990000; P:amyloid fibril formation; ISO:RGD.
DR GO; GO:0008637; P:apoptotic mitochondrial changes; ISO:RGD.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEP:RGD.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; ISO:RGD.
DR GO; GO:0090398; P:cellular senescence; ISO:RGD.
DR GO; GO:0021549; P:cerebellum development; IEP:RGD.
DR GO; GO:0008544; P:epidermis development; ISO:RGD.
DR GO; GO:0042593; P:glucose homeostasis; ISO:RGD.
DR GO; GO:0030889; P:negative regulation of B cell proliferation; ISO:RGD.
DR GO; GO:0045786; P:negative regulation of cell cycle; ISO:RGD.
DR GO; GO:0030308; P:negative regulation of cell growth; ISO:RGD.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISO:RGD.
DR GO; GO:0001953; P:negative regulation of cell-matrix adhesion; ISO:RGD.
DR GO; GO:0045736; P:negative regulation of cyclin-dependent protein serine/threonine kinase activity; ISO:RGD.
DR GO; GO:2000346; P:negative regulation of hepatocyte proliferation; IMP:RGD.
DR GO; GO:0033088; P:negative regulation of immature T cell proliferation in thymus; ISO:RGD.
DR GO; GO:0033600; P:negative regulation of mammary gland epithelial cell proliferation; ISO:RGD.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISO:RGD.
DR GO; GO:0042326; P:negative regulation of phosphorylation; ISO:RGD.
DR GO; GO:0032091; P:negative regulation of protein binding; ISO:RGD.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; ISO:RGD.
DR GO; GO:2000435; P:negative regulation of protein neddylation; ISO:RGD.
DR GO; GO:1903051; P:negative regulation of proteolysis involved in protein catabolic process; ISO:RGD.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISO:RGD.
DR GO; GO:1904667; P:negative regulation of ubiquitin protein ligase activity; ISO:RGD.
DR GO; GO:2000059; P:negative regulation of ubiquitin-dependent protein catabolic process; ISO:RGD.
DR GO; GO:0051444; P:negative regulation of ubiquitin-protein transferase activity; ISO:RGD.
DR GO; GO:0022008; P:neurogenesis; IEP:RGD.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:RGD.
DR GO; GO:0060058; P:positive regulation of apoptotic process involved in mammary gland involution; ISO:RGD.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; ISO:RGD.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD.
DR GO; GO:2000111; P:positive regulation of macrophage apoptotic process; ISO:RGD.
DR GO; GO:0033235; P:positive regulation of protein sumoylation; ISO:RGD.
DR GO; GO:0034393; P:positive regulation of smooth muscle cell apoptotic process; ISO:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:RGD.
DR GO; GO:0031648; P:protein destabilization; ISO:RGD.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; ISS:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; ISO:RGD.
DR GO; GO:0007265; P:Ras protein signal transduction; ISO:RGD.
DR GO; GO:1902510; P:regulation of apoptotic DNA fragmentation; ISO:RGD.
DR GO; GO:0051726; P:regulation of cell cycle; ISO:RGD.
DR GO; GO:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; ISO:RGD.
DR GO; GO:0051090; P:regulation of DNA-binding transcription factor activity; ISO:RGD.
DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; ISO:RGD.
DR GO; GO:0010389; P:regulation of G2/M transition of mitotic cell cycle; ISO:RGD.
DR GO; GO:0010468; P:regulation of gene expression; ISO:RGD.
DR GO; GO:0046822; P:regulation of nucleocytoplasmic transport; ISO:RGD.
DR GO; GO:0031647; P:regulation of protein stability; ISO:RGD.
DR GO; GO:0090399; P:replicative senescence; ISO:RGD.
DR GO; GO:0061771; P:response to caloric restriction; IEP:RGD.
DR GO; GO:0070542; P:response to fatty acid; IEP:RGD.
DR GO; GO:0014070; P:response to organic cyclic compound; IDA:RGD.
DR GO; GO:0010033; P:response to organic substance; IEP:RGD.
DR GO; GO:0010243; P:response to organonitrogen compound; IDA:RGD.
DR GO; GO:0009651; P:response to salt stress; IEP:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IDA:RGD.
DR GO; GO:0006364; P:rRNA processing; IEA:UniProtKB-KW.
DR GO; GO:0009303; P:rRNA transcription; ISO:RGD.
DR GO; GO:0048103; P:somatic stem cell division; ISO:RGD.
DR GO; GO:0035019; P:somatic stem cell population maintenance; ISO:RGD.
DR InterPro; IPR010868; Tumor_suppres_ARF.
DR Pfam; PF07392; P19Arf_N; 1.
PE 2: Evidence at transcript level;
KW Alternative splicing; Apoptosis; Cell cycle; DNA-binding; Nucleus;
KW Reference proteome; rRNA processing; Transcription;
KW Transcription regulation; Tumor suppressor; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1..160
FT /note="Tumor suppressor ARF"
FT /id="PRO_0000144183"
FT REGION 1..63
FT /note="Interaction with CDK5RAP3 and MDM2"
FT /evidence="ECO:0000250|UniProtKB:Q8N726"
FT REGION 49..74
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 90..116
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ SEQUENCE 160 AA; 17307 MW; 5A211F8315A66306 CRC64;
MGRRFVVTVR IRRTGRSPQV RVFLVQFLGS SRPRSANGTR GFVALVLRPE RIARRGPQPH
PGPGDDDGQR QSGSSPALLW CRFELRGPHH PLPTGARRSA GGLPRHSGST APGRGAAGCA
RCLGSPAARP GPRAGTSRRR AVFAVSTLLR WERFPGHRQA
