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p38 phosphorylates Rb on Ser567 by a novel, cell cycle-independent mechanism that triggers Rb–Hdm2 interaction and apoptosis

Oncogene volume 30, pages 588–599 (2011)Cite this article

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Abstract

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.

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Acknowledgements

We thank Doug Dean and members of the Harbour Lab for helpful discussions. This work was supported by the Vision Training Grant 5T32EY013360-09, and grants from the NIH (EY013169-09), the Barnes-Jewish Hospital Foundation, the Horncrest Foundation, The Kling Family Foundation and a Research to Prevent Blindness David F Weeks Professorship. This work was also supported by awards to the Department of Ophthalmology and Visual Sciences at Washington University from a Research to Prevent Blindness Inc. Unrestricted grant, and the NIH Vision Core Grant P30 EY 02687.

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  1. Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, MO, USA

    R B Delston, K A Matatall, Y Sun, M D Onken & J W Harbour

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Delston, R., Matatall, K., Sun, Y. et al. p38 phosphorylates Rb on Ser567 by a novel, cell cycle-independent mechanism that triggers Rb–Hdm2 interaction and apoptosis. Oncogene 30, 588–599 (2011). https://doi.org/10.1038/onc.2010.442

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