title: Nutlin-3 down-regulates retinoblastoma protein expression and inhibits muscle cell differentiation.
abstract: The p53 tumor suppressor gene plays a critical role in regulation of proliferation, cell death and differentiation. The MDM2 oncoprotein is a major negative regulator for p53 by binding to and targeting p53 for proteasome-mediated degradation. The small molecule inhibitor, nutlin-3, disrupts MDM2-p53 interaction resulting in stabilization and activation of p53 protein. We have previously shown that nutlin-3 activates p53, leading to MDM2 accumulation as concomitant of reduced retinoblastoma (Rb) protein stability. It is well known that Rb is important in muscle development and myoblast differentiation and that rhabdomyosarcoma (RMS), or cancer of the skeletal muscle, typically harbors MDM2 amplification. In this study, we show that nutlin-3 inhibited myoblast proliferation and effectively prevented myoblast differentiation, as evidenced by lack of expression of muscle differentiation markers including myogenin and myosin heavy chain (MyHC), as well as a failure to form multinucleated myotubes, which were associated with dramatic increases in MDM2 expression and decrease in Rb protein levels. These results indicate that nutlin-3 can effectively inhibit muscle cell differentiation.
authors: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
authors: Erica M
authors: EM
authors: Walsh
authors: Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610014 China.
authors: MengMeng
authors: M
authors: Niu
authors: Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610014 China.
authors: Johann
authors: J
authors: Bergholz
authors: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA; Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610014 China. Electronic address: jxiao@bu.edu.
authors: Zhi-Xiong Jim
authors: ZX
authors: Xiao
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D024510:Muscle Development / Q000187:drug effects; D032446:Myoblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D016160:Retinoblastoma Protein / Q000032:analysis / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D016160:Retinoblastoma Protein; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; Muscle differentiation; Nutlin; Rb