Distinct mechanisms for regulating the tumor suppressor and antiapoptotic functions of Rb.
The retinoblastoma protein, Rb, suppresses tumorigenesis by inhibiting cell proliferation and promoting senescence and differentiation. Paradoxically, Rb also inhibits apoptosis, which would seem to oppose its tumor suppressor function. Further, most human cancer cells inactivate Rb by hyperphosphorylation and demonstrate increased proliferative capacity but not high levels of apoptosis. As a potential explanation for these findings, we show here that the tumor suppressor and antiapoptotic functions of Rb are regulated by distinct phosphorylation events. Phosphorylation of sites in the C terminus occurs efficiently every cell cycle and regulates proliferation. Phosphorylation of Ser567 is inefficient and does not occur during the normal cell cycle. However, high cyclin-dependent kinase activity promotes phosphorylation of Ser567 by inducing an intramolecular interaction that leads to release of E2F, degradation of Rb, and susceptibility to apoptosis. Thus, phosphorylation of Ser567 may limit excessive proliferation by triggering cell death under hyperproliferative conditions. These findings suggest that the antiproliferative and antiapoptotic activities of Rb may represent complementary functions that work in concert to maintain the proliferation rate of cells within certain limits. As a survival strategy, some cancer cells may exploit this dual role of Rb by phosphorylating sites that regulate tumor suppression but avoiding phosphorylation of Ser567 and consequent apoptotic stimulus.
Ma
Duanduan
D
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Zhou
Ping
P
Harbour
J William
JW
D000595:Amino Acid Sequence; D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005347:Fibroblasts; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D007376:Interleukin-2; D015850:Interleukin-6; D051379:Mice; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D012516:Osteosarcoma; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D016415:Sequence Alignment; D014162:Transfection; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D007376:Interleukin-2; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; C089276:recombinant fusion protein IL-6 - IL-2; D010768:Phosphoserine; D018844:Cyclin-Dependent Kinases