Sci. Aging Knowl. Environ., 28 May 2003
Vol. 2003, Issue 21, p. nw75
[DOI: 10.1126/sageke.2003.21.nw75]

NOTEWORTHY ARTICLES

Rise to Power

Known gene regulator turns out to play crucial role in building smooth muscle cells

Mary Beckman

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/21/nw75

Key Words: myocytes • homodimerization • transcriptional activator • atherosclerosis • CArG box

As the master directs the student's paintbrush, a particular protein focuses another molecule's efforts. Together, the mentor and apprentice create smooth muscle, new research shows. Scientists knew that the instructor protein--called myocardin--helps activate smooth muscle cell genes, but they've now discovered that it is so powerful, it can turn skin cells into smooth muscle. The discovery might help researchers tame wanton smooth muscle cells that exacerbate age-related cardiovascular disease.

Smooth muscle cells make blood vessels tough yet flexible. When cholesterol, smoking, or high blood pressure damages arteries, inflammation turns these cells bad, which fosters plaque formation. The molecule that prods smooth muscle cells to behave normally has long eluded researchers, hampering their ability to understand how to stop the cells from weakening vessels.

One candidate for this master regulator is serum response factor (SRF). Discovered a decade ago, this protein activates genes required for smooth muscle development and growth, but it also flips on genes in other tissues, including skeletal muscle. Two years ago, researchers discovered myocardin, which works with SRF to turn on genes only in smooth muscle. Wang and colleagues wanted to test whether myocardin bestows a smooth muscle fate on cells.

To do so, the group assessed whether myocardin could awaken smooth muscle genes in cultured skin cells, which don't normally tap these genes. When the team produced myocardin in the skin cells, they assumed a muscle cell-like shape. Furthermore, they manufactured proteins normally observed in smooth muscle and did not produce certain proteins made by skeletal muscle cells. This finding indicates that myocardin focuses SRF on smooth muscle genes and suggests that myocardin is the key to smooth muscle cell development and growth.

Additional experiments revealed that disrupting the union between SRF and myocardin shuts down the smooth muscle program. The researchers engineered myocardin to lack different parts and tested the ability of these mutant regulators to prod cultured progenitor cells to mature into smooth muscle cells. Myocardin molecules without a region that sticks to SRF could not stimulate the transformation. In addition, myocardin molecules that couldn't clasp each other could not activate a smooth muscle test gene, suggesting that two or more myocardin proteins must hook up to do their job. Further results bolster that notion. SRF sits on a DNA sequence--a CArG box--that's found in many genes but that typically appears in pairs in smooth muscle genes. Myocardin triggered a test gene if it carried two CArG elements but not if it contained only one.

"This is the first time someone has found a specific way of turning nonmuscle cells into smooth muscle cells," says cardiologist Roger Hajjar of Massachusetts General Hospital in Boston, and the finding should allow researchers to study how these cells specialize. "The next step is to look at the status of these proteins in the disease state." Such studies might determine, for example, whether overzealous myocardin causes cardiovascular problems. Having discovered that myocardin is the chief artist, researchers might now find a way to alter its lesson plan.

--Mary Beckman


May 28, 2003
  1. Z. Wang, D.-Z. Wang, G. C. T. Pipes, E. N. Olson, Myocardin is a master regulator of smooth muscle gene expression. Proc. Natl. Acad. Sci. U.S.A., 19 May 2003 [e-pub ahead of print]. [Abstract] [Full Text]
  2. T. Yoshida et al., Myocardin is a key regulator of CArG-dependent transcription of multiple smooth muscle marker genes. Circ. Res. 92, 856-864 (2003). [Abstract/Free Full Text]
Citation: M. Beckman, Rise to Power. Sci. SAGE KE 2003, nw75 (28 May 2003)
http://sageke.sciencemag.org/cgi/content/full/sageke;2003/21/nw75








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