May 8, 2007 The skin's ability to replace the tissue it sloughs off is controlled by a variety of genes. A new study from Harvard Medical School published in the May 4 issue of Cell, however, identifies a "master regulator" of this regeneration process not only for skin, but for many epithelial tissues including breast, prostate, and urogenital tract.
This master regulator of epithelial stem cells turns out to be the p63 gene, a close relative to the well-known tumor-suppressing p53 gene. Without p63, mutant mice run out of the regenerative epithelial stem cells. The findings also have implications for cancers of the skin, breast and prostate, which are among the most common human malignancies.
The role of p63 in epithelial stem cells has been controversial. Some studies found that p63 maintains a steady pool of the regenerative cells, while other studies argued that p63 has more to do with causing the cells to differentiate into particular types of tissue. The study, which was lead by Frank McKeon, PhD, professor of cell biology at Harvard Medical School (HMS), shows that p63's role in not in tissue differentiation but rather to impart "stemness" to the regenerative cells in these tissues.
"With the p63-lacking mice you get normal commitment and differentiation," says McKeon. "The defect is simply running out of stem cells. When you run out of stem cells, you run out of those tissues as we have seen with the mice lacking the p63 gene."
Having established that p63 was only important to the maintenance of stem cells, McKeon and his research team then used the epithelial stem cell cloning methods developed by Howard Green, MD, the George Higginson professor of cell biology at HMS, to show that p63's key function was to provide the enhanced potential of stem cells to divide.
"The fact that p63 is essential for these epithelial stem cells, while other master regulators have been identified for blood stem cells and spermatocyte stem cells, suggests a fundamental requirement for tissue specificity of these regulators that we don't understand," says McKeon. "Dissecting the genetic programs controlled by these regulators will tell us much about how stem cells function and how they go awry in cancer."
This work was supported by the National Institutes of Health.
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