D-type cyclins, in association with the cyclin-dependent kinases Cdk4 or Cdk6, promote progression through the G1 phase of the cell cycle by phosphorylating the retinoblastoma protein (RB). The activities of Cdk4 and Cdk6 are constrained by inhibitors such as p16, the product of the CDKN2 gene on human chromosome 9p21 (refs 12-14). The frequent deletion or mutation of CDKN2 in tumour cells suggests that p16 acts as a tumour suppressor. We show that wild-type p16 arrests normal diploid cells in late G1, whereas a tumour-associated mutant of p16 does not. Significantly, the ability of p16 to induce cell-cycle arrest is lost in cells lacking functional RB, including primary fibroblasts from Rb-/- mouse embryos. Thus, loss of p16, overexpression of D-cyclins and loss of RB have similar effects on G1 progression, and may represent a common pathway to tumorigenesis.

• MeSH
• buněčný cyklus * fyziologie   MeSH
• cyklin D1 MeSH
• cyklin-dependentní kinasa 4 MeSH
• cyklin-dependentní kinasa 6 MeSH
• cyklin-dependentní kinasy * MeSH
• cykliny fyziologie   MeSH
• Escherichia coli MeSH
• G1 fáze fyziologie   MeSH
• inhibitor p16 cyklin-dependentní kinasy MeSH
• klonování DNA MeSH
• kultivované buňky MeSH
• lidé MeSH
• mikroinjekce MeSH
• mutace MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• onkogenní proteiny fyziologie   MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   MeSH
• protoonkogenní proteiny * MeSH
• rekombinantní proteiny metabolismus   MeSH
• retinoblastomový protein * fyziologie   MeSH
• transportní proteiny fyziologie   genetika   MeSH
• tumor supresorové geny * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH

The p16INK4/CDKN2, D-type cyclins, their partner cyclin-dependent kinases, and retinoblastoma protein constitute a G1 regulatory pathway commonly targeted in oncogenesis. We show that, unexpectedly, abnormalities of p16INK4/CDKN2 occur concomitantly in two-thirds of cancer cell lines harboring aberrations of cyclin D1. Gene and protein transfer experiments demonstrated that concurrent alterations of cyclin D1 and p16 levels cooperate to (de)regulate G1 control in diploid fibroblasts, and that both events influence growth of retinoblastoma (RB)-positive, but not RB-deficient cancer cells. These results show that biological consequences of deregulating individual components along the pathway are unequal, reflecting their hierarchical roles in the G1 checkpoint control. Whereas RB defects eliminate the checkpoint completely, aberrations of the upstream components, such as cyclin D1 and p16INK4/CDKN2, can cooperate in multistep tumorigenesis.

• MeSH
• buněčné dělení fyziologie   MeSH
• chromozomální aberace MeSH
• cyklin D1 MeSH
• cykliny genetika   fyziologie   MeSH
• G1 fáze fyziologie   MeSH
• inhibitor p16 cyklin-dependentní kinasy MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• nádorové buňky kultivované MeSH
• nádory genetika   patologie   MeSH
• onkogenní proteiny genetika   fyziologie   MeSH
• regulace genové exprese u nádorů MeSH
• sekvence nukleotidů MeSH
• transportní proteiny genetika   fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH