Format

Send to

Choose Destination
Mol Cell. 2016 Oct 6;64(1):25-36. doi: 10.1016/j.molcel.2016.08.015. Epub 2016 Sep 15.

The N-Terminal Phosphorylation of RB by p38 Bypasses Its Inactivation by CDKs and Prevents Proliferation in Cancer Cells.

Author information

1
Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
2
Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain; Departament de Ciències Experimentals i de la Salut, UPF, 08003 Barcelona, Spain.
3
Structural Bioinformatics Group (GRIB), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
4
Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain. Electronic address: eulalia.nadal@upf.edu.
5
Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain. Electronic address: francesc.posas@upf.edu.

Abstract

Control of the G1/S phase transition by the Retinoblastoma (RB) tumor suppressor is critical for the proliferation of normal cells in tissues, and its inactivation is one of the most fundamental events leading to cancer. Cyclin-dependent kinase (CDK) phosphorylation inactivates RB to promote cell cycle-regulated gene expression. Here we show that, upon stress, the p38 stress-activated protein kinase (SAPK) maximizes cell survival by downregulating E2F gene expression through the targeting of RB. RB undergoes selective phosphorylation by p38 in its N terminus; these phosphorylations render RB insensitive to the inactivation by CDKs. p38 phosphorylation of RB increases its affinity toward the E2F transcription factor, represses gene expression, and delays cell-cycle progression. Remarkably, introduction of a RB phosphomimetic mutant in cancer cells reduces colony formation and decreases their proliferative and tumorigenic potential in mice.

PMID:
27642049
DOI:
10.1016/j.molcel.2016.08.015
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center