Myc down-regulation as a mechanism to activate the Rb pathway in STAT5A-induced senescence

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Abstract

Senescence is a general antiproliferative program that avoids the expansion of cells bearing oncogenic mutations. We found that constitutively active STAT5A (ca-STAT5A) can induce a p53- and Rb-dependent cellular senescence response. However, ca-STAT5A did not induce p21 and p16INK4a, which are responsible for inhibiting cyclin-dependent protein kinases and engaging the Rb pathway during the senescence response to oncogenic ras. Intriguingly, ca-STAT5A led to a down-regulation of Myc and Myc targets, including CDK4, a negative regulator of Rb. The down-regulation of Myc was in part proteasome-dependent and correlated with its localization to promyelocytic leukemia bodies, which were found to be highly abundant during STAT5-induced senescence. Introduction of CDK4 or Myc bypassed STAT5A-induced senescence in cells in which p53 was also inactivated. These results uncover a novel mechanism to engage the Rb pathway in oncogene-induced senescence and indicate the existence of oncogene-specific pathways that regulate senescence. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

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Mallette, F. A., Gaumont-Leclerc, M. F., Huot, G., & Ferbeyre, G. (2007). Myc down-regulation as a mechanism to activate the Rb pathway in STAT5A-induced senescence. Journal of Biological Chemistry, 282(48), 34938–34944. https://doi.org/10.1074/jbc.M707074200

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