View source for P14arf

{{Short description|Human protein}}
{{about|a tumor suppressor gene|ARF small GTP-binding protein|ADP ribosylation factor}}
{{Lowercase title}}
{{infobox protein
|Name=cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)
|caption=
|image=
|width=
|HGNCid=1787
|Symbol=CDKN2A
|AltSymbols=CDKN2, MLM
|EntrezGene=1029
|OMIM=600160
|RefSeq=NM_058195
|UniProt=P42771
|PDB=
|ECnumber=
|Chromosome=9
|Arm=p
|Band=21
|LocusSupplementaryData=
}}
'''p14ARF''' (also called '''ARF tumor suppressor''', '''ARF''', '''p14<sup>ARF</sup>''') is an '''a'''lternate '''r'''eading '''f'''rame protein product of the ''[[P16 (gene)|CDKN2A]]'' locus (i.e. ''INK4a''/''ARF'' locus).<ref name='Sherr 2006b'>{{cite journal |author=Sherr CJ |title=Divorcing ARF and p53: an unsettled case |journal=Nat. Rev. Cancer |volume=6 |issue=9 |pages=663–73 |date=September 2006 |pmid=16915296 |doi=10.1038/nrc1954 |s2cid=29465278 }}</ref> p14ARF is induced in response to elevated [[mitogenic]] stimulation, such as aberrant growth signaling from [[MYC]] and [[Ras (protein)]].<ref name='Abida'>{{cite journal |vauthors=Abida WM, Gu W |title=p53-Dependent and p53-independent activation of autophagy by ARF |journal=Cancer Res. |volume=68 |issue=2 |pages=352–7 |date=January 2008 |pmid=18199527 |doi=10.1158/0008-5472.CAN-07-2069 |pmc=3737745 }}</ref> 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 gene|tumor suppressor]] by inhibiting [[ribosome]] biogenesis or initiating [[p53]]-dependent [[cell cycle]] arrest and [[apoptosis]], respectively.<ref name='Sherr 2006a'>{{cite journal |author=Sherr CJ |title=Autophagy by ARF: a short story |journal=Mol. Cell |volume=22 |issue=4 |pages=436–7 |date=May 2006 |pmid=16713573 |doi=10.1016/j.molcel.2006.05.005 |doi-access=free }}</ref> 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,<ref name='Sherr 2006b'/> and it is polyubiquinated at the [[N-terminus]].<ref name='Kuo'>{{cite journal |vauthors=Kuo ML, den Besten W, Bertwistle D, Roussel MF, Sherr CJ |title=N-terminal polyubiquitination and degradation of the Arf tumor suppressor |journal=Genes Dev. |volume=18 |issue=15 |pages=1862–74 |date=August 2004 |pmid=15289458 |pmc=517406 |doi=10.1101/gad.1213904 }}</ref>
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]]-[[Cyclin-dependent kinase|CDK]] complexes, which would otherwise promote [[Transcription (genetics)|transcription]] of [[gene]]s that would carry the [[cell (biology)|cell]] through the [[Cell cycle checkpoint#Restriction Checkpoint|G<sub>1</sub>/S checkpoint]] of the cell cycle.  Loss of p14ARF by a [[Mutation#By inheritance|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.
==Background==
The p14ARF transcript was first identified in humans in 1995,<ref name='Stone'>{{cite journal |author=Stone S |title=Complex structure and regulation of the P16 (MTS1) locus |journal=Cancer Res. |volume=55 |issue=14 |pages=2988–94 |date=July 1995 |pmid=7606716 |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=7606716 |name-list-style=vanc|author2=Jiang P |author3=Dayananth P |display-authors=3 |last4=Tavtigian |first4=SV |last5=Katcher |first5=H |last6=Parry |first6=D |last7=Peters |first7=G |last8=Kamb |first8=A}}</ref><ref name='Mao'>{{cite journal |author=Mao L |title=A novel p16<sup>INK4A</sup> transcript |journal=Cancer Res. |volume=55 |issue=14 |pages=2995–7 |date=July 1995 |pmid=7541708 |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=7541708 |name-list-style=vanc|author2=Merlo A |author3=Bedi G |display-authors=3 |last4=Shapiro |first4=GI |last5=Edwards |first5=CD |last6=Rollins |first6=BJ |last7=Sidransky |first7=D}}</ref> and its [[protein]] product confirmed in mice that same year.<ref name='Quelle'>{{cite journal |vauthors=Quelle DE, Zindy F, Ashmun RA, Sherr CJ |title=Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest |journal=Cell |volume=83 |issue=6 |pages=993–1000 |date=December 1995 |pmid=8521522 |doi= 10.1016/0092-8674(95)90214-7 |s2cid=14839001 |doi-access=free }}</ref> Its gene locus is on the short arm of [[chromosome 9]] in humans, and on a corresponding location on chromosome 4 in mice.<ref name='Sherr 2006b'/>  It is located near the [[genes]] for the tandem repeats INK4a and INK4b, which are 16 kDa (p16<sup>INK4a</sup>) and 15 kDa (p15<sup>INK4b</sup>) 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 phase([[S phase]]).<ref name='Sherr 2001'>{{cite journal |author=Sherr CJ |title=The INK4a/ARF network in tumour suppression |journal=Nat. Rev. Mol. Cell Biol. |volume=2 |issue=10 |pages=731–7 |date=October 2001 |pmid=11584300 |doi=10.1038/35096061 |s2cid=26220426 }}</ref> Therefore, INK4a and INK4b serve as tumor suppressors by restricting proliferation though the inhibition of the CDKs responsible for Rb [[phosphorylation]].<ref name='Quelle'/>
In addition to the INK4a protein, the unrelated protein, ARF, is transcribed from an alternate [[reading frame]] at the INK4a/ARF locus.<ref name='Sherr 2006b'/> 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 INK4b.<ref name='Sherr 2006b'/> 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 (biology)|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 protein.<ref name='Sherr 2006b'/> When the ARF β-transcript was found, it was thought that it probably would not encode a protein.<ref name="Stone"/><ref name='Mao'/> In humans, ARF is translated into the 14kDa, 132 amino acid [[p14<sup>ARF</sup>]] protein, and in mice, it is translated into the 19kDa, 169 amino acid p19<sup>Arf</sup>.<ref name='Sherr 2006b'/> 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 identity.<ref name='Quelle'/>
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 humans).<ref name='Sherr 2001'/> 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 advantage.<ref name='Sherr 2006b'/>
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 Mdm2.<ref name='Bertwistle'>{{cite journal |vauthors=Bertwistle D, Sugimoto M, Sherr CJ |title=Physical and Functional Interactions of the Arf Tumor Suppressor Protein with Nucleophosmin/B23 |journal=Mol. Cell. Biol. |volume=24 |issue=3 |pages=985–96 |date=February 2004 |pmid=14729947 |pmc=321449 |doi= 10.1128/MCB.24.3.985-996.2004}}</ref>  In 2004  has been found that one of ARF's p53-independent functions involves its binding to [[nucleophosmin]]/B23 (NPM).<ref name='Bertwistle'/> NPM is an acidic [[ribosomal]] [[chaperone (protein)]] involved in preribosomal processing and nuclear exportation independent of p53, and oligomerizes with itself and p14<sup>ARF</sup>. Nearly half of p14<sup>ARF</sup> 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 p14<sup>ARF</sup> can bind to NPM, inhibiting rRNA processing.<ref name='Bertwistle'/> ARF-null cells have increased nucleolar area, increased [[ribosome]] biogenesis, and a corresponding increase in [[protein]] synthesis.<ref name='Apicelli'>{{cite journal |author=Apicelli AJ |title=A Non-Tumor Suppressor Role for Basal p14ARF in Maintaining Nucleolar Structure and Function |journal=Mol. Cell. Biol. |volume=28 |issue=3 |pages=1068–80 |date=February 2008 |pmid=18070929 |pmc=2223401 |doi=10.1128/MCB.00484-07 |name-list-style=vanc|author2=Maggi LB |author3=Hirbe AC |display-authors=3 |last4=Miceli |first4=A. P. |last5=Olanich |first5=M. E. |last6=Schulte-Winkeler |first6=C. L. |last7=Saporita |first7=A. J. |last8=Kuchenreuther |first8=M. |last9=Sanchez |first9=J.}}</ref> 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 proliferation.<ref name='Apicelli'/>
==Role in Disease==
Very commonly, cancer is associated with a loss of function of INK4a, ARF, Rb, or [[p53]].<ref name='Lowe'>{{cite journal |vauthors=Lowe SW, Sherr CJ |title=Tumor suppression by Ink4a-Arf: progress and puzzles |journal=Curr. Opin. Genet. Dev. |volume=13 |issue=1 |pages=77–83 |date=February 2003 |pmid=12573439 |doi= 10.1016/S0959-437X(02)00013-8}}</ref> 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 p14<sup>ARF</sup> defects.<ref name='Yi'>{{cite journal |vauthors=Yi Y, Shepard A, Kittrell F, Mulac-Jericevic B, Medina D, Said TK |title=p19ARF Determines the Balance between Normal Cell Proliferation Rate and Apoptosis during Mammary Gland Development |journal=Mol. Biol. Cell |volume=15 |issue=5 |pages=2302–11 |date=May 2004 |pmid=15105443 |pmc=404024 |doi=10.1091/mbc.E03-11-0785 }}</ref> In a separate study, 32% of colorectal [[adenomas]] (non-cancerous tumors) were found to have p14<sup>ARF</sup> inactivation due to hyper[[methylation]] of the [[Promoter (biology)|promoter]]. Mouse models lacking p19<sup>Arf</sup>, p53, and Mdm2 are more prone to tumor development than mice without Mdm2 and p53, alone. This suggests that p19<sup>Arf</sup> has Mdm2- and p53-independent effects, as well.<ref name='Weber'>{{cite journal |author=Weber JD |title=p53-independent functions of the p19ARF tumor suppressor |journal=Genes Dev. |volume=14 |issue=18 |pages=2358–65 |date=September 2000 |pmid=10995391 |pmc=316930 |doi= 10.1101/gad.827300|name-list-style=vanc|author2=Jeffers JR |author3=Rehg JE |display-authors=3 |last4=Randle |first4=DH |last5=Lozano |first5=G |last6=Roussel |first6=MF |last7=Sherr |first7=CJ |last8=Zambetti |first8=GP}}</ref> Investigating this idea lead to the recent discovery of smARF.<ref name='Reef 2006'>{{cite journal |author=Reef S |title=A short mitochondrial form of p19<sup>ARF</sup> induces autophagy and caspase-independent cell death |journal=Mol. Cell |volume=22 |issue=4 |pages=463–75 |date=May 2006 |pmid=16713577 |doi=10.1016/j.molcel.2006.04.014 |name-list-style=vanc|author2=Zalckvar E |author3=Shifman O |display-authors=3 |last4=Bialik |first4=Shani |last5=Sabanay |first5=Helena |last6=Oren |first6=Moshe |last7=Kimchi |first7=Adi|doi-access=free }}</ref>
Homozygous deletions and other mutations of CDK2NA (ARF) have been found to be associated with [[glioblastoma]].<ref>{{cite journal|last=Cancer Genome Atlas Research|first=Network|title=Comprehensive genomic characterization defines human glioblastoma genes and core pathways.|journal=Nature|date=Oct 23, 2008|volume=455|issue=7216|pages=1061–8|pmid=18772890|doi=10.1038/nature07385|pmc=2671642|bibcode=2008Natur.455.1061M}}</ref>
==smARF==
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, smARF.<ref name='Reef 2006'/> 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 death.<ref name='Reef 2007'>{{cite journal |vauthors=Reef S, Shifman O, Oren M, Kimchi A |title=The autophagic inducer smARF interacts with and is stabilized by the mitochondrial p32 protein |journal=Oncogene |volume=26 |issue=46 |pages=6677–83 |date=October 2007 |pmid=17486078 |doi=10.1038/sj.onc.1210485 |doi-access=free }}</ref>
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 rats, 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 [[isoform]].<ref name='Reef 2006'/> The role of smARF is distinct from that of ARF, as it lacks the [[nuclear localization signal]] (NLS) and cannot bind to [[Mdm2]] or NPM.<ref name='Sherr 2006a'/> 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]] activation.<ref name='Abida'/>
==Biochemistry==
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 loss.<ref name='Sherr 2001'/> 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 increases.<ref name='Lowe'/> ARF is negatively regulated by Rb-E2F complexes <ref name='Lowe'/> and by amplified p53 activation.<ref name='Sherr 2001'/> Aberrant growth signals also increase smARF expression.<ref name='Reef 2007'/>
ARF is a highly basic (pI>12) and [[hydrophobic]] protein.<ref name='Sherr 2001'/> 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 known.<ref name='Sherr 2006b'/> 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 changes.<ref name='Sherr 2006b'/>
The [[half-life]] of ARF is about 6 hours,<ref name='Kuo'/> while the half-life of smARF is less than 1 hour.<ref name='Sherr 2006a'/> Both [[isoforms]] are degraded in the [[proteasome]].<ref name='Sherr 2006b'/><ref name='Kuo'/> ARF is targeted for the [[proteasome]] by [[N-terminus]] [[ubiquitylation]].<ref name='Kuo'/> Proteins are usually ubiquinated at [[lysine]] residues. Human [[p14<sup>ARF</sup>]], however, does not contain any lysines, and mouse p19<sup>Arf</sup> 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 p19<sup>Arf</sup> (Met-Gly-Arg) and p14<sup>ARF</sup> (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 ubiquination.<ref name='Sherr 2006b'/>
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 machinery.<ref name='Kuo'/> The [[mitochondrial matrix]] protein p32 stabilizes smARF.<ref name='Reef 2007'/> 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 p19<sup>Arf</sup> are not affected by p32 knockdown, and so p32 specifically stabilizes smARF, possibly by protecting it from the [[proteasome]] or from [[mitochondrial]] [[proteases]].<ref name='Reef 2007'/>
== References ==
{{Reflist}}
Zhang, Y., Y. Xiong, and W.G. Yarbrough.  ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways. Cell 1998, 92(6):725-34.
==Further reading==
*{{cite journal |vauthors=Bertwistle D, Sherr CJ |title=Regulation of the Arf tumor suppressor in Emicro-Myc transgenic mice: longitudinal study of Myc-induced lymphomagenesis |journal=Blood |volume=109 |issue=2 |pages=792–4 |date=January 2007 |pmid=16968893 |doi=10.1182/blood-2006-07-033985 |doi-access=free }}
*{{cite journal |author=Codogno P |title=Autophagy and caspase-independent cell death: p19ARF enters the game |journal=Dev. Cell |volume=10 |issue=6 |pages=688–9 |date=June 2006 |pmid=16740471 |doi=10.1016/j.devcel.2006.05.003 |doi-access=free }}
*{{cite journal |author=Esteller M |title=Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status |journal=Cancer Res. |volume=60 |issue=1 |pages=129–33 |date=January 2000 |pmid=10646864 |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10646864 |name-list-style=vanc|author2=Tortola S |author3=Toyota M |display-authors=3 |last4=Capella |first4=G |last5=Peinado |first5=MA |last6=Baylin |first6=SB |last7=Herman |first7=JG}}
*{{cite journal |author=Menéndez S |title=Oligomerization of the human ARF tumor suppressor and its response to oxidative stress |journal=J. Biol. Chem. |volume=278 |issue=21 |pages=18720–9 |date=May 2003 |pmid=12582152 |doi=10.1074/jbc.M211007200 |name-list-style=vanc|author2=Khan Z |author3=Coomber DW |display-authors=3 |last4=Lane |first4=DP |last5=Higgins |first5=M |last6=Koufali |first6=MM |last7=Lain |first7=S|doi-access=free }}
*{{cite journal |vauthors=Szklarczyk R, Heringa J, Pond SK, Nekrutenko A |title=Rapid asymmetric evolution of a dual-coding tumor suppressor INK4a/ARF locus contradicts its function |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=104 |issue=31 |pages=12807–12 |date=July 2007 |pmid=17652172 |pmc=1937548 |doi=10.1073/pnas.0703238104 |bibcode=2007PNAS..10412807S |doi-access=free }}
*{{cite journal |vauthors=Zhang Y, Xiong Y |title=Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53 |journal=Mol. Cell |volume=3 |issue=5 |pages=579–91 |date=May 1999 |pmid=10360174 |doi= 10.1016/S1097-2765(00)80351-2|doi-access=free }}
*{{cite journal|last1=Tan|first1=X|last2=Anzick|first2=SL|last3=Khan|first3=SG|last4=Ueda|first4=T|last5=Stone|first5=G|last6=Digiovanna|first6=JJ|last7=Tamura|first7=D|last8=Wattendorf|first8=D|last9=Busch|first9=D|last10=Brewer|first10=CC|last11=Zalewski|first11=C|last12=Butman|first12=JA|last13=Griffith|first13=AJ|last14=Meltzer|first14=PS|last15=Kraemer|first15=KH|title=Chimeric negative regulation of p14ARF and TBX1 by a t(9;22) translocation associated with melanoma, deafness, and DNA repair deficiency|journal=Hum Mutat|date=2013|volume=34|issue=9|pages=1250–9|doi=10.1002/humu.22354|pmid=23661601|pmc=3746749}}
== External links ==
* {{MeshName|Tumor+Suppressor+Protein+p14ARF}}
{{Tumor suppressor genes}}
{{Cell cycle proteins}}