The Institute of Genetics and CytologyNortheast Normal UniversityChangchun130024China
Zhu S.,The Institute of Genetics and CytologyNortheast Normal UniversityChangchun130024China |
Zhao L.,The Key Laboratory of Molecular Epigenetics of the Ministry of EducationNortheast Normal UniversityChangchun130020China |
Li Y.,The Institute of Genetics and CytologyNortheast Normal UniversityChangchun130024China |
Hou P.,The Institute of Genetics and CytologyNortheast Normal UniversityChangchun130024China |
And 6 more authors.
Journal of Cellular Biochemistry | Year: 2015
Cellular senescence impedes cancer progression by limiting uncontrolled cell proliferation. To identify new genetic events controlling senescence, we performed a small interfering RNA screening human cancer cells and identified a number of targets potentially involved in senescence of MDA-MB-231 human breast cancer cells. Importantly, we showed that knockdown of RAD21 resulted in the appearance of several senescent markers, including enhanced senescence-associated β-galactosidase activity and heterochromatin focus formation, as well as elevated p21 protein levels and RB1 pathway activation. Further biochemical analyses revealed that RAD21 knockdown led to the downregulation of c-Myc and its targets, including CDK4, a negative regulator of RB1, and blockedRB1 phosphorylation (pRB1), and the RB1-mediated transcriptional repression of E2F. Moreover, c-Myc downregulation was partially mediated by proteasome-dependent degradation within promyelocytic leukemia (PML) nuclear bodies, which were found to be highly abundant during RAD21 knockdown-induced senescence. Exogenous c-Myc reconstitution rescued cells from RAD21 silencing-induced senescence. Altogether, data arising from this study implicate a novel function of RAD21 in cellular senescence in MDA-MB-231 cells that is mainly dependent onRB1 pathway activation via c-Myc downregulation. © 2015 Wiley Periodicals, Inc.