TY - JOUR
T1 - p16INK4a, but not constitutively active pRb, can impose a sustained G1 arrest: molecular mechanisms and implications for oncogenesis.
AU - Lukas, J
AU - Storgaard Sørensen, Claus
AU - Lukas, C
AU - Santoni-Rugiu, E
AU - Bartek, J
N1 - Keywords: Animals; CDC2-CDC28 Kinases; Cell Transformation, Neoplastic; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinases; G1 Phase; Gene Transfer Techniques; Growth Inhibitors; Humans; Osteosarcoma; Protein-Serine-Threonine Kinases; Rats; Retinoblastoma Protein; S Phase; Tumor Cells, Cultured
PY - 1999
Y1 - 1999
N2 - 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.
AB - 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.
U2 - 10.1038/sj.onc.1202777
DO - 10.1038/sj.onc.1202777
M3 - Journal article
C2 - 10435615
SN - 0950-9232
VL - 18
SP - 3930
EP - 3935
JO - Oncogene
JF - Oncogene
IS - 27
ER -