p16INK4a, but not constitutively active pRb, can impose a sustained G1 arrest: molecular mechanisms and implications for oncogenesis.
p16ink4 and pRb, two components of a key G1/S regulatory pathway, and tumor suppressors commonly targeted in oncogenesis, are among the candidates for gene therapy of cancer. Wild-type p16 and a constitutively active pRb(delta cdk) mutant both blocked G1 in short-term experiments, but only p16 imposed a sustained G1 arrest. Unexpectedly, cells conditionally exposed to pRb(delta cdk) entered S phase after 2 days, followed by endoreduplication between days 4-6. The distinct phenotypes evoked by p16 vs pRb(delta cdk) appear mediated by cyclin E/CDK2 which, while active in the pRb(delta cdk)-expressing cells, became rapidly inhibited through restructuring diverse cyclin/CDK/p21 complexes by p16. These results provide novel insights into the roles of p16, pRb and cyclin E in G1/S control and multistep oncogenesis, with implications for gene therapy strategies.
Lukas
J
J
Institute of Cancer Biology, Danish Cancer Society, Copenhagen.
Sørensen
C S
CS
Lukas
C
C
Santoni-Rugiu
E
E
Bartek
J
J
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis / Q000378:metabolism; D016193:G1 Phase / Q000235:genetics / Q000502:physiology*; D018014:Gene Transfer Techniques; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D012516:Osteosarcoma; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016196:S Phase / Q000235:genetics; D014407:Tumor Cells, Cultured
D019941:Cyclin-Dependent Kinase Inhibitor p16; D006131:Growth Inhibitors; D016160:Retinoblastoma Protein; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases