A decade later, gene discovered by Temple researchers found to be multi-functional

A gene discovered by Temple University researchers a decade ago has proved to be multi-functional, with the discovery of its important roles in cell differentiation, HIV transcription, and tumorigenesis.

Cdk9 (cyclin-dependent kinases) and cdk10 were originally isolated by Antonio Giordano, M.D., Ph.D., then a researcher in Temple’s Fels Cancer Institute, and his team in 1992. They are members of a family of kinases originally referred to as a PITALRE, which is the name of the amino acids sequence that is similar to all in this kinase family (http://landesbioscience.com/journals/cancerbio/papersinpress/1.4/cbt03040266.html).

“We were screening a human DNA library in order to look for members of this family and we found cdk9, a gene that encodes for a protein that has the size of 43 kilodaltons,” says Giordano, now director of the Sbarro Institute for Cancer Research and Molecular Medicine in Temple’s College of Science and Technology (http://www.temple.edu/news_media/hkg696.html).

Over the next 10 years, cdk9 would prove to be a “multi-functional” gene, playing many different roles.

According to Giordano, among the many functions of cdk9 that have been discovered, one of the most interesting is the role of this kinase in cellular differentiation, particularly muscle differentiation.

“In practical terms, when we overexpress this protein, we are able to promote myogenic differentiation by enhancing the myoD function,” says Giordano, who also discovered the tumor suppressing gene Rb2/p130. “Our studies demonstrate that in human tissue, cdk9 is a very important player in specialized tissue, such as muscle or lymphoid tissue.”

Another important discovery, says Giordano, shows that if cdk9 is inhibited, or blocked, it prevents the promotion of differentiation, suggesting that this kinase plays a central role in controlling muscle differentiation by regulating directly, genes and their products, such as myoD that is specific for muscle.

“Cdk9 is not only involved in this muscle program, but its specific role in muscle differentiation is important in other programs, such as neurons and astrocytes maturation,” he adds. “In addition, cdk9 has been found by several researchers to play a clinical role in other important processes such as apoptosis and in the regulation of the HIV protein Tat.”

More recently, based on the discovery of cdk9’s role in muscle differentiation, Giordano collaborated with Dr. Michael D. Schneider of the DeBakey Heart Center at the Baylor University College of Medicine, who demonstrated that cdk9 can be used to block life-threatening hypertrophy or enlargement of the heart. Their study was published in the November 2002 issue of Nature Medicine (www.nature.com/cgi-taf/DynaPage.taf?file=/nm/journal/v8/n11/abs/nm778.html).

An immunologic role for cdk9 has also been discovered and was reported this past fall in Oncogene by Giordano in collaboration with Professor Piero Tosi’s group at the University of Siena in Italy. They have shown that it interacts with gp130, the receptor of the Interleukin-6 (IL-6) family of cytokines.

This discovery, says Dr. Michele Maio, Director of the Cancer Bioimmunotherapy Unit of the Centro di Riferimento Oncologico of Aviano in Italy and adjunct professor at Temple, highlights a totally new biologic role of cdk9. “This should allow us to take advantage of IL-6 as therapeutic agents for targeted therapy in selected histotypes of human cancer.”

“Cdk9 acts preferentially by controlling processes such as transcription and the balance between differentiation and apoptosis (programmed cell death), suggesting the important role this kinase can have in controlling or blocking important cellular processes. This is important also from a clinical point of view,” concludes Giordano, a cancer specialist who is now actively investigating the role of cdk9 in cancer.

Initial clinical trials of a potent inhibitor of cdk9 function, flavopiridol, are now underway at the National Institutes of Health’s National Cancer Institute (NIH/NCI) in collaboration with Aventis Pharmaceutics. Dr. Adrian M. Senderowicz, Principal Investigator and Chief, Molecular Therapeutics Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, conducted the first clinical trials with this agent at NIH’s Clinical Center.

Based on his encouraging results, several clinical trials worldwide are now being conducted, with a Phase 3 clinical trial in lung cancer being carried out at different research centers in the world, assuring that the multi-functional legacy of cdk9 continues to grow well into the future.