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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. - Highlights: • Nutlin-3 inhibits myoblast proliferation and prevents differentiation into myotubes. • Nutlin-3 increases MDM2 expression and down-regulates Rb protein levels. • This study has implication in nutlin-3 treatment of rhabdomyosarcomas.

Authors:
 [1]; ;  [2];  [1];  [3]
  1. Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118 (United States)
  2. Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610014 China (China)
  3. (China)
Publication Date:
OSTI Identifier:
22462060
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 461; Journal Issue: 2; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BUILDUP; CELL DIFFERENTIATION; CELL PROLIFERATION; CONNECTIVE TISSUE; FAILURES; GENES; INTERACTIONS; MOLECULES; MUSCLES; MYOSIN; REGULATIONS; RHABDOMYOSARCOMAS; STABILITY

Citation Formats

Walsh, Erica M., Niu, MengMeng, Bergholz, Johann, Jim Xiao, Zhi-Xiong, E-mail: jxiao@bu.edu, and Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610014 China. Nutlin-3 down-regulates retinoblastoma protein expression and inhibits muscle cell differentiation. United States: N. p., 2015. Web. doi:10.1016/J.BBRC.2015.04.024.
Walsh, Erica M., Niu, MengMeng, Bergholz, Johann, Jim Xiao, Zhi-Xiong, E-mail: jxiao@bu.edu, & Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610014 China. Nutlin-3 down-regulates retinoblastoma protein expression and inhibits muscle cell differentiation. United States. doi:10.1016/J.BBRC.2015.04.024.
Walsh, Erica M., Niu, MengMeng, Bergholz, Johann, Jim Xiao, Zhi-Xiong, E-mail: jxiao@bu.edu, and Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610014 China. Fri . "Nutlin-3 down-regulates retinoblastoma protein expression and inhibits muscle cell differentiation". United States. doi:10.1016/J.BBRC.2015.04.024.
@article{osti_22462060,
title = {Nutlin-3 down-regulates retinoblastoma protein expression and inhibits muscle cell differentiation},
author = {Walsh, Erica M. and Niu, MengMeng and Bergholz, Johann and Jim Xiao, Zhi-Xiong, E-mail: jxiao@bu.edu and Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610014 China},
abstractNote = {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. - Highlights: • Nutlin-3 inhibits myoblast proliferation and prevents differentiation into myotubes. • Nutlin-3 increases MDM2 expression and down-regulates Rb protein levels. • This study has implication in nutlin-3 treatment of rhabdomyosarcomas.},
doi = {10.1016/J.BBRC.2015.04.024},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 2,
volume = 461,
place = {United States},
year = {2015},
month = {5}
}