Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 40, Pages 29962-29971Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M605445200
Keywords
-
Categories
Funding
- NIDDK NIH HHS [R01 DK042748, R01 DK42748] Funding Source: Medline
Ask authors/readers for more resources
The insulin-like growth factors (IGFs) play key roles in muscle development, maintenance, and repair, but their mechanisms of action are incompletely defined. We previously identified an autocrine pathway involving production of IGF-II and activation of the IGF-I receptor, phosphatidylinositol 3-kinase, and Akt in myoblast differentiation induced by MyoD in 10T1/2 mesenchymal stem cells and found that blocking this pathway prevented differentiation ( Wilson, E. M., Hsieh, M. M., and Rotwein, P. ( 2003) J. Biol. Chem. 278, 41109 - 41113). We now have analyzed regulation of MyoD function in this model system. Inhibition of IGF-II production impaired the transcriptional actions of MyoD, as seen by a 70-80% decline in activity of transfected reporter genes, including the myogenin and creatine kinase promoters, and by complete inhibition of transcription of the endogenous myogenin gene but had no effect on MyoD protein levels, post-translational modifications, or nuclear localization, and neither blocked the rapid disappearance of the inhibitory molecule Id1 nor altered the nuclear expression or abundance of the MyoD binding partner E12/E47. Impaired signaling through the IGF-I receptor also did not decrease the ability of MyoD or E12/E47 to bind to target DNA sites at the proximal myogenin promoter, as assessed by chromatin immunoprecipitation assay but, rather, blocked chromatin remodeling at this site, as indicated by reduced recruitment of co-activators p300 and P/CAF and diminished acetylation of histones H3 and H4. Taken together, these results show that IGF-II-initiated signaling through the insulin-like growth factor-I receptor targets transcriptional co-regulators that are essential co-factors for MyoD and suggests that the phosphatidylinositol 3-kinase-Akt pathway plays a key role in establishing an amplification cascade that is essential for sustaining the earliest events in muscle differentiation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available