Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest

Ouelle, Dawn E.; Zindy, Frédérique; Ashmun, Richard A.; Sherr, Charles J.

doi:10.1016/0092-8674(95)90214-7

Cited by 1,375 publications

(1,116 citation statements)

References 37 publications

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“…These and other ®ndings reported in the present study have both clinical and basic importance. Before discussing them, however, it should be mentioned that the MST-1/INK4a locus also has recently been shown to encode for a second tumor suppressor protein, namely p19-ARF, which uses the same MST-1/INK4a second exon with an alternate reading frame as is utilized to produce p16 (Quelle et al, 1995). Moreover, as both gene products are often mutated in the same tumor, one might question if p19-ARF loss could also be related to the RB overexpression seen in p16 negative tumors.…”

Section: Discussionmentioning

confidence: 99%

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

et al. 1999

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Recent studies have shown that patients whose bladder cancer exhibit overexpression of RB protein as measured by immunohistochemical analysis do equally poorly as those with loss of RB function. We hypothesized that loss of p16 protein function could be related to RB overexpression, since p16 can induce transcriptional downregulation of RB and its loss may lead to aberrant RB regulation. Conversely, loss of RB function has been associated with high p16 protein expression in several other tumor types. In the present study RB negative bladder tumors also exhibited strong nuclear p16 staining while each tumor with strong, homogeneous RB nuclear staining were p16 negative, supporting our hypothesis. To expand on these immunohistochemical studies additional cases were selected in which the status of the p16 encoding gene had been determined at the molecular level. Absent p16 and high RB protein expression was found in the tumors having loss of heterozygosity within 9p21 and a structural change (mutation or deletion) of the remaining p16 encoding gene allele, con®rming the staining results. These results strongly support the hypothesis that the RB nuclear overexpression recently associated with poor prognosis in bladder cancer is also associated with loss of p16 function and implies that loss of p16 function could be equally deleterious as RB loss in bladder and likely other cancers.

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Section: Discussionmentioning

confidence: 99%

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

et al. 1999

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“…P14 ARF (p19 ARF in the mouse) was originally identified as the alternative transcript of the human INK4a tumor suppressor locus, which also encodes the cdk inhibitor p16 INK4a (Mao et al, 1995;Quelle et al, 1995). Although sharing exons 2 and 3, p14 ARF and p16 INK4a are structurally and functionally completely unrelated, as transcription of p14 ARF initiates at a separate exon 1b and proceeds in an alternative reading frame (ARF).…”

Section: Introductionmentioning

confidence: 99%

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

et al. 2006

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In contrast to the initial notion that the biological activity of p14 ARF strictly depends on a functional mdm-2/p53 signaling axis, we recently demonstrated that p14 ARF mediates apoptosis in a p53/Bax-independent manner. Here, we show that p14 ARF induces breakdown of the mitochondrial membrane potential and cytochrome c release before triggering caspase-9-and caspase-3/7-like activities in p53/Bax-deficient DU145 prostate cancer cells expressing wild-type Bak. Re-expression of Bax in these cells failed to further enhance p14 ARF -induced apoptosis, suggesting that p14 ARF -induced apoptosis primarily depends on Bak but not Bax in these cells. To further define the role of Bak and Bax in p14 ARF -induced mitochondrial apoptosis, we employed short interference RNA for the knockdown of bak in isogeneic, p53 wildtype HCT116 colon cancer cells either proficient or deficient for Bax. There, combined loss of Bax and Bak attenuated p14 ARF -induced apoptosis whereas single loss of Bax or Bak was only marginally effective, as in the case of DU145. Notably, HCT116 cells deficient for Bax and Bak failed to release cytochrome c and showed attenuated activation of caspase-9 (LEHDase) and caspase-3/caspase-7 (DEVDase) upon p14 ARF expression. These data indicate that p14 ARF triggers apoptosis via a Bax/Bakdependent pathway in p53-proficient HCT116, whereas Bax is dispensable in p53-deficient DU145 cells. Nevertheless, a substantial proportion of p14 ARF -induced cell death proceeds in a Bax/Bak-independent manner. This is also the case for inhibition of clonogenic growth that occurs, at least in part, through an entirely Bax/Bakindependent mechanism.

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“…The p53 pathway can be activated by inappropriate growth signals generated by a number of activated viral and cellular oncogenes (Lowe, 1999;Prives and Hall, 1999;Lomax and Fried, 2001;Sherr and McCormick, 2002;O'Shea and Fried, 2005). This latter response can be mediated by the ARF protein (p14ARF in human and p19ARF in rodents), which is specified by the alternative reading frame transcript of the p16 INK4A gene in the CDNK2A Locus (Quelle et al, 1995). ARF is inactivated in a variety of human tumors, consistent with its role as a tumor suppressor (Ruas and Peters, 1998;Sherr, 2004).…”

Section: Introductionmentioning

confidence: 93%

Chromosomal instability at a mutational hotspot in polyoma middle T-antigen affects its ability to activate the ARF-p53 tumor suppressor pathway

et al. 2005

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We have isolated spontaneous mutants of polyoma virus middle T-antigen (PyMT) that do not activate the ARFp53 pathway based on their inability to block REF52 cell division. The REF52 cells containing these mutants have a flat untransformed morphological phenotype and do not express the ARF protein. The PyMT mutations in the different cell isolates so far analysed occur at a mutational hotspot in the PyMT sequence between nucleotides 1241 and 1249, which contains nine consecutive cytosines. In one set of mutants a single cytosine was deleted, while in another mutant set an additional cytosine was inserted. Both these mutations result in frameshifts, generating altered PyMT proteins containing amino-acid sequences derived from each of the two other alternative reading frames of the polyoma virus early region. Both types of mutations result in the loss of the C-terminal PyMT region containing the membrane-binding hydrophobic region and result is mislocalization of the PyMT mutant proteins. Revertant wild-type PyMT (containing nine cytosines) was easily detected in transformants generated after infection of REF52 cells expressing high amounts of dominant negative p53 with retroviruses containing either mutation. We demonstrate that wild-type PyMT revertants are derived from mutations in the hotspot sequence of the integrated mutant PyMT sequences.

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Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest

Cited by 1,375 publications

References 37 publications

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

Chromosomal instability at a mutational hotspot in polyoma middle T-antigen affects its ability to activate the ARF-p53 tumor suppressor pathway

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