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p14arf

p14arf acts as an antagonist of hmga2, p14arf methylation
p14ARF also called ARF tumor suppressor, ARF, p14ARF is an alternate reading frame protein product of the CDKN2A locus ie INK4a/ARF locus1 p14ARF is induced in response to elevated mitogenic stimulation, such as aberrant growth signaling from MYC and Ras protein2 It accumulates mainly in the nucleolus where it forms stable complexes with NPM or Mdm2 These interactions allow p14ARF to act as a tumor suppressor by inhibiting ribosome biogenesis or initiating p53-dependent cell cycle arrest and apoptosis, respectively3 p14ARF is an atypical protein, in terms of its transcription, its amino acid composition, and its degradation: it is transcribed in an alternate reading frame of a different protein, it is highly basic,1 and it is polyubiquinated at the N-terminus4

Both p16INK4a and p14ARF are involved in cell cycle regulation p14ARF inhibits mdm2, thus promoting p53, which promotes p21 activation, which then binds and inactivates certain cyclin-CDK complexes, which would otherwise promote transcription of genes that would carry the cell through the G1/S checkpoint of the cell cycle Loss of p14ARF by a homozygous mutation in the CDKN2A INK4A gene will lead to elevated levels in mdm2 and, therefore, loss of p53 function and cell cycle control

The equivalent in mice is p19ARF

Contents

  • 1 Background
  • 2 Role in Disease
  • 3 smARF
  • 4 Biochemistry
  • 5 References
  • 6 Further reading
  • 7 External links

Backgroundedit

The p14ARF transcript was first identified in humans in 1995,56 and its protein product confirmed in mice that same year7 Its gene locus is on the short arm of chromosome 9 in humans, and on a corresponding location on chromosome 4 in mice1 It is located near the genes for the tandem repeats INK4a and INK4b, which are 16 kDa p16INK4a and 15 kDa p15INK4b proteins, respectively These INK4 proteins directly inhibit the cyclin D-dependent kinases CDK4 and CDK6 There are other INK4 genes on other chromosomes, however these are not linked to cancer, and so their functions are not likely to be overlapping An important cyclin-dependent substrate is the retinoblastoma protein Rb, which is phosphorylated in late gap 1 phase G1 phase, allowing G1 exit The Rb protein limits cell proliferation by blocking the activity of E2F transcription factors, which activate the transcription of genes needed for DNA replication When Rb is phosphorylated by cyclin D and E-dependent kinases during the G1 phase of the cell cycle, Rb can not block E2F-dependent transcription, and the cell can progress to the DNA synthetic phaseS phase8 Therefore, INK4a and INK4b serve as tumor suppressors by restricting proliferation though the inhibition of the CDKs responsible for Rb phosphorylation7

In addition to the INK4a protein, the unrelated protein, ARF, is transcribed from an alternate reading frame at the INK4a/ARF locus1 INK4a and p14ARF mRNA each consist of three exons They share exons 2 and 3, but there are two different exon 1 transcripts, α and β Exon 1β E1β is intercalated between the genes for INK4a and INK4b1 Although exon 1α E1α and E1β are about the same in terms of content and size, the 5’ AUG start codon of exon 1β has its own promoter and opens an alternative reading frame in exon 2, hence the name p14ARF ARF exon 3 is not translated Because of this, INK4a and p14ARF have unrelated amino acid sequences despite overlapping coding regions, and have distinct functions This dual use of coding sequences is not commonly seen in mammals, making p14ARF an unusual protein1 When the ARF β-transcript was found, it was thought that it probably would not encode a protein56 In humans, ARF is translated into the 14kDa, 132 amino acid p14ARF protein, and in mice, it is translated into the 19kDa, 169 amino acid p19Arf1 The E1β protein segment of mouse and human ARF are 45% identical, with an overall ARF identity of 50%, compared to a 72% identity between mouse and human INK4a E1α segment, and a 65% overall identity7

Although the INK4a and ARF proteins are structurally and functionally different, they are both involved in cell cycle progression Together, their broad inhibitory role may help counter oncogenic signals As mentioned above, INK4a inhibits proliferation by indirectly allowing Rb to remain associated with E2F transcription factors ARF is involved in p53 activation by inhibiting Mdm2 HDM2 in humans8 Mdm2 binds to p53, inhibiting its transcriptional activity Mdm2 also has E3 ubiquitin ligase activity toward p53, and promotes its exportation from the cell nucleus to the cytoplasm for degradation By antagonizing Mdm2, ARF permits the transcriptional activity of p53 that would lead to cell cycle arrest or apoptosis A loss of ARF or p53, therefore, would give cells a survival advantage1

The function of ARF has primarily been attributed to its Mdm2/p53 mechanism ARF does, however, also inhibit proliferation in cells lacking p53 or p53 and Mdm29 It has recently been found that one of ARF’s p53-independent functions involves its binding to nucleophosmin/B23 NPM9 NPM is an acidic ribosomal chaperone protein involved in preribosomal processing and nuclear exportation independent of p53, and oligomerizes with itself and p14ARF Nearly half of p14ARF is found in NPM-containing complexes with high molecular mass 2 to 5 MDa Enforced expression of ARF retards early 47S/45S rRNA precursor processing and inhibits 32S rRNA cleavage This suggests that p14ARF can bind to NPM, inhibiting rRNA processing9 ARF-null cells have increased nucleolar area, increased ribosome biogenesis, and a corresponding increase in protein synthesis10 The larger size resulting from more ribosomes and protein is not associated with increased proliferation, however, and this ARF-null phenotype occurs even though the normal basal levels of Arf are usually low Knocking down ARF with siRNA to exon 1β results in increased rRNA transcripts, rRNA processing, and ribosome nuclear export The unrestrained ribosome biogenesis seen when NPM is not bound to ARF does not occur if NPM is also absent Although the induction of ARF in response to oncogenic signals is considered to be of primary importance, the low levels of ARF seen in interphase cells also has a considerable effect in terms of keeping cell growth in check Therefore, the function of basal level ARF in the NPM/ARF complex appears to be to monitor steady-state ribosome biogenesis and growth independently of preventing proliferation10

Role in Diseaseedit

Very commonly, cancer is associated with a loss of function of INK4a, ARF, Rb, or p5311 Without INK4a, Cdk4/6 can inappropriately phosphorylate Rb, leading to increased E2F-dependent transcription Without ARF, Mdm2 can inappropriately inhibit p53, leading to increased cell survival

The INK4a/ARF locus is found to be deleted or silenced in many kinds of tumors For example, of the 100 primary breast carcinomas, approximately 41% have p14ARF defects12 In a separate study, 32% of colorectal adenomas non-cancerous tumors were found to have p14ARF inactivation due to hypermethylation of the promoter Mouse models lacking p19Arf, p53, and Mdm2 are more prone to tumor development than mice without Mdm2 and p53, alone This suggests that p19Arf has Mdm2- and p53-independent effects, as well13 Investigating this idea lead to the recent discovery of smARF14

Homozygous deletions and other mutations of CDK2NA ARF have been found to be associated with glioblastoma15

smARFedit

Until recently, the two known effects of ARF were growth inhibition by NPM interactions and apoptosis induction by Mdm2 interactions The function of ARF involving p53-independent death, has now been attributed to the small mitochondrial isoform of ARF, smARF14 While full-length ARF inhibits cell growth by cell cycle arrest or type I apoptotic death, smARF kills cells by type II autophagic death Like ARF, the expression of smARF increases when there are aberrant proliferation signals When smARF is overexpressed, it localizes to the mitochondrial matrix, damaging the mitochondria membrane potential and structure, and leading to autophagic cell death16

The translation of the truncated ARF, smARF, is initiated at an internal methionine M45 of the ARF transcript in human and mouse cells SmARF is also detected in rat, even though an internal methionine is not present in the rat transcript This suggests that there is an alternate mechanism to form smARF, underscoring the importance of this isoform14 The role of smARF is distinct from that of ARF, as it lacks the nuclear localization signal NLS and cannot bind to Mdm2 or NPM3 In some cell types, however, full-length ARF can also localize to the mitochondria and induce type II cell death, suggesting that in addition to autophagy being a starvation or other environmental response, it may also be involved in responding to oncogene activation2

Biochemistryedit

ARF expression is regulated by oncogenic signaling Aberrant mitogenic stimulation, such as by MYC or Ras protein, will increase its expression, as will an amplification of mutated p53 or Mdm2, or p53 loss8 ARF can also be induced by enforced E2F expression Although E2F expression is increased during the cell cycle, ARF expression probably is not because the activation of a second, unknown transcription factor might be needed to prevent an ARF response to transient E2F increases11 ARF is negatively regulated by Rb-E2F complexes 11 and by amplified p53 activation8 Aberrant growth signals also increase smARF expression16

ARF is a highly basic pI>12 and hydrophobic protein8 Its basic nature is attributed to its arginine content; more than 20% of its amino acids are arginine, and it contains little or no lysine Due to these characteristics, ARF is likely to be unstructured unless it is bound to other targets It reportedly complexes with more than 25 proteins, although the significance of each of these interactions is not known1 One of these interactions results in sumoylating activity, suggesting that ARF may modify proteins to which it binds The SUMO protein is a small ubiquitin-like modifier, which is added to lysly ε-amino groups This process involves a three-enzyme cascade similar to the way ubiquitylation occurs E1 is an activating enzyme, E2 is a conjugation enzyme, and E3 is a ligase ARF associates with UBC9, the only SUMO E2 known, suggesting ARF facilitates SUMO conjugation The importance of this role is unknown, as sumoylation is involved in different functions, such as protein trafficking, ubiquitylation interference, and gene expression changes1

The half-life of ARF is about 6 hours,4 while the half-life of smARF is less than 1 hour3 Both isoforms are degraded in the proteasome14 ARF is targeted for the proteasome by N-terminus ubiquitylation4 Proteins are usually ubiquinated at lysine residues Human p14ARF, however, does not contain any lysines, and mouse p19Arf only contains one lysine If the mouse lysine is replaced with arginine, there is no effect on its degradation, suggesting it is also ubiquinated at the N-terminus This adds to the uniqueness of the ARF proteins, because most eukaryotic proteins are acetylated at the N-terminus, preventing ubiquination at this location Penultimate residues affect the efficiency of acetylation, in that acetylation is promoted by acidic residues and inhibited by basic ones The N-terminal amino acid sequences of p19Arf Met-Gly-Arg and p14ARF Met-Val-Arg would be processed by methionine aminopeptidase but would not be acetylated, allowing ubiquination to proceed The sequence of smARF, however, predicts that the initiating methionine would not be cleaved by methionine aminopeptidase and would probably be acetylated, and so is degraded by the proteasome without ubiquination1

Full-length nucleolar ARF appears to be stabilized by NPM The NPM-ARF complex does not block the N-terminus of ARF, but likely protects ARF from being accessed by degradation machinery4 The mitochondrial matrix protein p32 stabilizes smARF16 This protein binds various cellular and viral proteins, but its exact function is unknown Knocking down p32 dramatically decreases smARF levels by increasing its turnover The levels of p19Arf are not affected by p32 knockdown, and so p32 specifically stabilizes smARF, possibly by protecting it from the proteasome or from mitochondrial proteases16

Referencesedit

  1. ^ a b c d e f g h i j k l Sherr CJ September 2006 "Divorcing ARF and p53: an unsettled case" Nat Rev Cancer 6 9: 663–73 PMID 16915296 doi:101038/nrc1954 
  2. ^ a b Abida WM, Gu W January 2008 "p53-Dependent and p53-independent activation of autophagy by ARF" Cancer Res 68 2: 352–7 PMID 18199527 doi:101158/0008-5472CAN-07-2069 
  3. ^ a b c Sherr CJ May 2006 "Autophagy by ARF: a short story" Mol Cell 22 4: 436–7 PMID 16713573 doi:101016/jmolcel200605005 
  4. ^ a b c d e Kuo ML, den Besten W, Bertwistle D, Roussel MF, Sherr CJ August 2004 "N-terminal polyubiquitination and degradation of the Arf tumor suppressor" Genes Dev 18 15: 1862–74 PMC 517406  PMID 15289458 doi:101101/gad1213904 
  5. ^ a b Stone S, Jiang P, Dayananth P, et al July 1995 "Complex structure and regulation of the P16 MTS1 locus" Cancer Res 55 14: 2988–94 PMID 7606716 
  6. ^ a b Mao L, Merlo A, Bedi G, et al July 1995 "A novel p16INK4A transcript" Cancer Res 55 14: 2995–7 PMID 7541708 
  7. ^ a b c Quelle DE, Zindy F, Ashmun RA, Sherr CJ December 1995 "Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest" Cell 83 6: 993–1000 PMID 8521522 doi:101016/0092-86749590214-7 
  8. ^ a b c d e Sherr CJ October 2001 "The INK4a/ARF network in tumour suppression" Nat Rev Mol Cell Biol 2 10: 731–7 PMID 11584300 doi:101038/35096061 
  9. ^ a b c Bertwistle D, Sugimoto M, Sherr CJ February 2004 "Physical and Functional Interactions of the Arf Tumor Suppressor Protein with Nucleophosmin/B23" Mol Cell Biol 24 3: 985–96 PMC 321449  PMID 14729947 doi:101128/MCB243985-9962004 
  10. ^ a b Apicelli AJ, Maggi LB, Hirbe AC, et al February 2008 "A Non-Tumor Suppressor Role for Basal p14ARF in Maintaining Nucleolar Structure and Function" Mol Cell Biol 28 3: 1068–80 PMC 2223401  PMID 18070929 doi:101128/MCB00484-07 
  11. ^ a b c Lowe SW, Sherr CJ February 2003 "Tumor suppression by Ink4a-Arf: progress and puzzles" Curr Opin Genet Dev 13 1: 77–83 PMID 12573439 doi:101016/S0959-437X0200013-8 
  12. ^ Yi Y, Shepard A, Kittrell F, Mulac-Jericevic B, Medina D, Said TK May 2004 "p19ARF Determines the Balance between Normal Cell Proliferation Rate and Apoptosis during Mammary Gland Development" Mol Biol Cell 15 5: 2302–11 PMC 404024  PMID 15105443 doi:101091/mbcE03-11-0785 
  13. ^ Weber JD, Jeffers JR, Rehg JE, et al September 2000 "p53-independent functions of the p19ARF tumor suppressor" Genes Dev 14 18: 2358–65 PMC 316930  PMID 10995391 doi:101101/gad827300 
  14. ^ a b c Reef S, Zalckvar E, Shifman O, et al May 2006 "A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death" Mol Cell 22 4: 463–75 PMID 16713577 doi:101016/jmolcel200604014 
  15. ^ Cancer Genome Atlas Research, Network Oct 23, 2008 "Comprehensive genomic characterization defines human glioblastoma genes and core pathways" Nature 455 7216: 1061–8 PMC 2671642  PMID 18772890 doi:101038/nature07385 
  16. ^ a b c d Reef S, Shifman O, Oren M, Kimchi A October 2007 "The autophagic inducer smARF interacts with and is stabilized by the mitochondrial p32 protein" Oncogene 26 46: 6677–83 PMID 17486078 doi:101038/sjonc1210485 

Further readingedit

  • Bertwistle D, Sherr CJ January 2007 "Regulation of the Arf tumor suppressor in Emicro-Myc transgenic mice: longitudinal study of Myc-induced lymphomagenesis" Blood 109 2: 792–4 PMID 16968893 doi:101182/blood-2006-07-033985 
  • Codogno P June 2006 "Autophagy and caspase-independent cell death: p19ARF enters the game" Dev Cell 10 6: 688–9 PMID 16740471 doi:101016/jdevcel200605003 
  • Esteller M, Tortola S, Toyota M, et al January 2000 "Hypermethylation-associated inactivation of p14ARF is independent of p16INK4a methylation and p53 mutational status" Cancer Res 60 1: 129–33 PMID 10646864 
  • Menéndez S, Khan Z, Coomber DW, et al May 2003 "Oligomerization of the human ARF tumor suppressor and its response to oxidative stress" J Biol Chem 278 21: 18720–9 PMID 12582152 doi:101074/jbcM211007200 
  • Szklarczyk R, Heringa J, Pond SK, Nekrutenko A July 2007 "Rapid asymmetric evolution of a dual-coding tumor suppressor INK4a/ARF locus contradicts its function" Proc Natl Acad Sci USA 104 31: 12807–12 PMC 1937548  PMID 17652172 doi:101073/pnas0703238104 
  • Zhang Y, Xiong Y May 1999 "Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53" Mol Cell 3 5: 579–91 PMID 10360174 doi:101016/S1097-27650080351-2 
  • Tan, X; Anzick, SL; Khan, SG; Ueda, T; Stone, G; Digiovanna, JJ; Tamura, D; Wattendorf, D; Busch, D; Brewer, CC; Zalewski, C; Butman, JA; Griffith, AJ; Meltzer, PS; Kraemer, KH 2013 "Chimeric negative regulation of p14ARF and TBX1 by a t9;22 translocation associated with melanoma, deafness, and DNA repair deficiency" Hum Mutat 34 9: 1250–9 PMC 3746749  PMID 23661601 doi:101002/humu22354 

External linksedit

  • Tumor Suppressor Protein p14ARF at the US National Library of Medicine Medical Subject Headings MeSH

p14arf acts as an antagonist of hmga2, p14arf antibody, p14arf cancer, p14arf gene, p14arf methylation, p14arf mutation


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p14arf


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    p14arf beatiful post thanks!

    29.10.2014


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