Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16

Lukáš, Jiří; Parry, David; Aagaard, Louise; Mann, David J.; Bártková, Jiřina; Strauß, Michael; Peters, Gordon; Bártek, Jiří

doi:10.1038/375503a0

Cited by 857 publications

(664 citation statements)

References 18 publications

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“…The explanation for this fact is that the suppressive potential of p110 RB is inactivated by phosphorylation, which can be inhibited by p16INK4 binding to the corresponding CDK [24]. Therefore, loss or alteration of p16INK4 expression would affect the functions of p110 RB .…”

Section: Discussionmentioning

confidence: 99%

Analysis of the p16INK4 and TP53 tumor suppressor genes in bone sarcoma pediatric patients

Patiño-García

Sierrasesúmaga

1997

Cancer Genetics and Cytogenetics

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Recent data suggest that deletion of p16INK4 and mutation of TP53 are among the most common genetic events in the development of human cancer, since the codified proteins act as brakes of the abnormal cell cycle. As the molecular events leading to the development of pediatric bone sarcomas remain unclear, we analyzed 75 osteosarcoma and Ewing sarcoma samples from 43 pediatric patients to search for alterations at the TP53 or p16INK4 tumor suppressor genes. By means of PCRDGGE (polymerase chain reaction and denaturing gradient gel electrophoresis) we detected TP53 point mutations in 18.6% of the tumor samples, but no constitutional mutations. In the analysis of p16INK4, 7% of the samples harbored deletions of the gene but no point mutations were detected by SSCP (single strand conformation polymorphism) analysis, just the polymorphism Ala -› Thr at codon 148. These data support the hypothesis that TP53 alterations may play a role in the development of pediatric bone tumors and that the primary mechanism of inactivation of p16INK4 seems to be homozygous deletion rather than point mutation.

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Section: Discussionmentioning

confidence: 99%

Analysis of the p16INK4 and TP53 tumor suppressor genes in bone sarcoma pediatric patients

Patiño-García

Sierrasesúmaga

1997

Cancer Genetics and Cytogenetics

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“…p16ink4a binds directly to CDK4 and CDK6 and displaces cyclin D1 from the complex (Serrano et al, 1993;Koh et al, 1995;Russo et al, 1998;Jeffrey et al, 2000). Through this ability to antagonize cyclin D1 function, p16ink4a blocks cell cycle progression, and the antiproliferative action of p16ink4a is dependent both on the presence of CDK4/6 activity and RB (Koh et al, 1995;Lukas et al, 1995b). Clinical analyses support a model wherein p16ink4a, cyclin D1 and RB fall in a common pathway (Figure 1), as loss of p16ink4a, loss of RB, or excessive activation of CDK4/cyclin D1 are mutually exclusive events in human cancers (Otterson et al, 1994;Kelley et al, 1995;Palmero and Peters, 1996).…”

Section: Cyclin D1 and Cell Cycle Controlmentioning

confidence: 99%

Cyclin D1: polymorphism, aberrant splicing and cancer risk

et al. 2006

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The cyclin D1 proto-oncogene exercises powerful control over the mechanisms that regulate the mitotic cell cycle, and excessive cyclin D1 expression and/or activity is common in human cancers. Although somatic mutations of the cyclin D1 locus are rarely observed, mounting evidence demonstrates that a specific polymorphism of cyclin D1 (G/A870) and a protein product of a potentially related alternate splicing event (cyclin D1b) may influence cancer risk and outcome. Herein, we review the epidemiological and functional literatures that link these alterations of cyclin D1 to human tumor development and progression.

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“…Okamoto et al, 1994;Otterson et al, 1994;Kratzke et al, 1996;Shapiro et al, 1995;Yeager et al, 1995;Sakaguchi et al, 1996). This p16 overexpression is likely caused by the absence of RB to downregulate p16 protein production, although p16 overexpression has no e ect in the absence of RB (Lukas et al, 1995).…”

Section: Introductionmentioning

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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Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16

Cited by 857 publications

References 18 publications

Analysis of the p16INK4 and TP53 tumor suppressor genes in bone sarcoma pediatric patients

Analysis of the p16INK4 and TP53 tumor suppressor genes in bone sarcoma pediatric patients

Cyclin D1: polymorphism, aberrant splicing and cancer risk

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

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