The long term objective of this research proposal is to seek a more complete understanding of the mechanisms through which extracellular signals regulate the growth and differentiation of skeletal muscle cells. Recent findings indicate that the differentiation process is under the control of a number of regulator genes. Enforced expression of these genes, even in normally nonmyogenic cell types, leads to the expression of differentiation markers. Available evidence suggests that these regulator genes may interact with other transcription factors to regulate muscle specific gene expression. Major advances have also been made in the field of signal transduction within the last five years. We and others have identified a set of primary response genes whose activation appears to be a critical step in several signal transduction pathways. Many of these primary response genes which include the protooncogenes c-fos and c-jun appear to be potential transcription factors. The apparent importance of the primary sponse genes in the muscle differentiation process is underscored by the observation that transformation of myogenic cells with c- fos inhibits their differentiation. The research program to be implemented during the grant period attempts to identify primary response genes that play a significant and specific role in regulating muscle differentiation and to define the mechanism(s) of their functional involvement. It will compare the expression and inducibility of these genes between proliferating myoblasts and differentiated myocytes to determine the molecular basis of the loss of mitogenic responsiveness following muscle differentiation. Knowledge gathered from this research should have intrinsic implications on the basic developmental echanisms regulating muscle cell growth and differentiation. In addition, the molecular basis of growth inhibition in terminally differentiated muscle cells might shed light on how antioncogenes might function in preventing tumorigenesis. Results from this project will also advance our understanding of the signal transduction systems that are employed under many biological contexts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AR040682-03
Application #
3457480
Study Section
Molecular Cytology Study Section (CTY)
Project Start
1991-08-01
Project End
1996-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Type
Schools of Medicine
DUNS #
112205955
City
Columbia
State
MO
Country
United States
Zip Code
65211
Chu, C Y; Lim, R W (2000) Involvement of p27(kip1) and cyclin D3 in the regulation of cdk2 activity during skeletal muscle differentiation. Biochim Biophys Acta 1497:175-85
Han, B H; Park, D J; Lim, R W et al. (1998) Cloning, expression, and characterization of a novel guanylate-binding protein, GBP3 in murine erythroid progenitor cells. Biochim Biophys Acta 1384:373-86
Chen, B; Han, B H; Sun, X H et al. (1997) Inhibition of muscle-specific gene expression by Id3: requirement of the C-terminal region of the protein for stable expression and function. Nucleic Acids Res 25:423-30
Yang, W L; Lim, R W (1997) Modulation of muscle creatine kinase promoter activity by the inducible orphan nuclear receptor TIS1. Biochem J 321 ( Pt 2):281-7
Montano, M M; Lim, R W (1997) Glucocorticoid effects on the skeletal muscle differentiation program: analysis of clonal proliferation, morphological differentiation and the expression of muscle-specific and regulatory genes. Endocr Res 23:37-57
Lim, R W; Zhu, C Y; Stringer, B (1995) Differential regulation of primary response gene expression in skeletal muscle cells through multiple signal transduction pathways. Biochim Biophys Acta 1266:91-100
Lim, R W; Yang, W L; Yu, H (1995) Signal-transduction-pathway-specific desensitization of expression of orphan nuclear receptor TIS1. Biochem J 308 ( Pt 3):785-9
Li, W B; Gruber, C E; Lin, J J et al. (1994) The isolation of differentially expressed genes in fibroblast growth factor stimulated BC3H1 cells by subtractive hybridization. Biotechniques 16:722-9
Park, D J; Lim, R W; Kim, H D (1993) Rapid induction of mouse virus-like (VL30) element transcripts by erythropoietin in murine erythroid progenitor cells. Blood 82:77-83
Tripathi, Y B; Lim, R W; Fernandez-Gallardo, S et al. (1992) Involvement of tyrosine kinase and protein kinase C in platelet-activating-factor-induced c-fos gene expression in A-431 cells. Biochem J 286 ( Pt 2):527-33