UCSD Researchers Discover Protein Essential For Formation Of Skin's Outer Layer

Published in the April 5, 2001 issue of the journal Nature, the research was conducted in the lab of Michael Karin, Ph.D., professor of pharmacology and a member of the UCSD Cancer Center. Karin is also an American Cancer Society Research Professor.

Using test-tube analysis and studies in mice, the researchers identified a protein called a keratinocyte differentiation-inducing factor, or kDIF, which is required for the production of the thin layer of fibrous (keratinized) epidermal cells on the skin’s surface. As scientists learn more about this protein, it may provide clues to skin cancer prevention or new methods for improved wound healing.

The discovery of the new protein is based on the Karin laboratory’s ongoing investigation of an important regulatory protein kinase complex called I-kappa-B kinase (or IKK), which they identified in late 1996, along with IKK’s three sub-units, alpha, beta and gamma. These enzymes regulate the function and metabolism of other proteins by adding chemical components called phosphate groups to them. Through their landmark work, and work done elsewhere, it has been shown that IKK controls the body’s inflammatory response, the first line of defense from microbial infections.

In research reported in 1999, the Karin team determined that the IKK-beta sub-unit and a protein called NF-kB are central players in the cascade of events leading to the inflammatory response. Unexpectedly, the IKK alpha sub-unit was found to control the proliferation and specialization of the skin’s basal cells, which lie in the base of the epidermis.

Normally, as they mature, basal cells work their way up through the epidermis and ultimately form the thin layer of keratinized cells on the skin surface. The absence of IKK-alpha results in uncontrolled production of basal cells and complete absence of the uppermost layer of keratinized skin cells. However, researchers still did not know the mechanism by which IKK-alpha worked.

“It is very important for basal cells to undergo a precise program of specialization, called differentiation, in order for the uppermost layer of skin to be formed,” Karin says, adding that the only, but very important, function of basal cells is to regenerate skin. In fact, basal cell carcinoma – a common form of skin cancer – is due to uncontrolled proliferation of basal cells.

Through differentiation, basal cells become specialized and migrate outward, making large amounts of keratinized structural proteins, which form the protective outer layer of the skin. This occurs only when the newly discovered protein, kDIF, is present.

The UCSD researchers found kDIF through experiments with mice bred to lack the IKK-alpha enzyme. Through elimination tests, they determined that the enzymatic ability of IKK-alpha was not a requirement for keratinized skin formation. To pinpoint the essential IKK-alpha element responsible for skin cell differentiation, the investigators transplanted embryonic mouse skin cells (without IKK-alpha) onto the skin of normal mice. Although abnormal at first, the IKK-alpha deficient skin grew hair and gained a normal appearance within four weeks, indicating that something in the normal skin was influencing normal growth in the adjacent transplanted skin. Further lab studies supported the existence of kDIF and the ability of IKK-alpha to control kDIF production.

The lead author of the Nature article is UCSD post-doctoral researcher Yinling Hu, Ph.D., who plans to continue study of kDIF’s role in skin cell differentiation and potential role in basal cell carcinoma. Additional UCSD authors were Veronique Baud, Ph.D.; Takefumi Oga, M.D., Ph.D.; Keun Ii Kim, Ph.D., and Kazuhiko Yoshida, Ph.D.

The work was supported by grants from the National Institutes of Health, the Association for International Cancer Research, and the CERIES Research Award to Karin.