Transcriptional Control Of Cell Differentiation

Studies have shown that both internal and external factors can regulate differentiation by mediating gene and protein expression. External compounds, such as growth factors, pharmaceutical agents, lipids, hormones, etc., influence cell differentiation through cascades that culminate in transcription factor activation followed by gene transcription.[2] This may be followed by translation of the gene product into a protein that induces the cell's phenotypic change. For example, thiazolidinediones are PPAR ligands that induce the transcription factor PPAR-g2, which induces adipocyte differentiation and protein production, including adipocyte lipid-binding protein (aP2) and leptin. Transforming growth factor (TGF) and bone morphogenic proteins (BMP) are examples of growth factors that induce transcription factors and alter gene expression in various cell types in domestic animals (Table 1). Sma- and Mad-related proteins (Smads) are activated by both the TGF and BMP superfamilies and have roles in the differentiation of several cell types.[3] Although some transcription factors, such as Jak/STAT, regulate similar processes in all cell types, it should be noted that transcription factors can have cell-specific effects. For example, CEBPs play roles in the differentiation of adipocytes, epithelial cells, and neutrophils.

Transcription factors in the MyoD muscle regulatory factor (MRF) family are responsible for muscle development and, when expressed, can induce myogenesis in nonmyogenic cell types.[4] Avian, bovine, and porcine studies have shown that MyoD and myogenin expression precede myotube formation. Muscle from double-muscled cattle expresses higher levels of MyoD and myostatin reflecting the importance of these factors in inhibiting proliferation. The interaction of various transcription factors is also key in regulating cell differentiation as shown by the myostatin-induced Smad3 phosphorylation and interaction with MyoD, which inhibits differentiation in cultured cells. Myostatin is also a potent inhibitor of Pax-3 and Myf-5, which are associated with proliferation, whereas follistatin promotes Pax3-enhanced proliferation in muscle. Alternatively, some transcription factors are involved in cellular processes other than terminal differentiation.

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