p38 phosphorylates Rb on Ser567 by a novel, cell cycle-independent mechanism that triggers Rb-Hdm2 interaction and apoptosis.
The retinoblastoma protein (Rb) inhibits both cell division and apoptosis, but the mechanism by which Rb alternatively regulates these divergent outcomes remains poorly understood. Cyclin-dependent kinases (Cdks) promote cell division by phosphorylating and reversibly inactivating Rb by a hierarchical series of phosphorylation events and sequential conformational changes. The stress-regulated mitogen-activated protein kinase p38 also phosphorylates Rb, but it does so in a cell cycle-independent manner that is associated with apoptosis rather than with cell division. Here, we show that p38 phosphorylates Rb by a novel mechanism that is distinct from that of Cdks. p38 bypasses the cell cycle-associated hierarchical phosphorylation and directly phosphorylates Rb on Ser567, which is not phosphorylated during the normal cell cycle. Phosphorylation by p38, but not Cdks, triggers an interaction between Rb and the human homolog of murine double minute 2 (Hdm2), leading to degradation of Rb, release of E2F1 and cell death. These findings provide a mechanistic explanation as to how Rb regulates cell division and apoptosis through different kinases, and reveal how Hdm2 may functionally link the tumor suppressors Rb and p53.
Delston
R B
RB
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, MO, USA.
Matatall
K A
KA
Sun
Y
Y
Onken
M D
MD
Harbour
J W
JW
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D000077546:Roscovitine; D012694:Serine / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D047428:Protein Kinase Inhibitors; D011687:Purines; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D000077546:Roscovitine; D012694:Serine; D005047:Etoposide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D048308:Mitogen-Activated Protein Kinase 14; D048051:p38 Mitogen-Activated Protein Kinases