Molecular Signaling Network a Promising Drug Target in Many Types of Tumors

Cancer researchers have identified a molecular signaling network present in many types of tumors that they suggest could be a promising target for a new generation of chemotherapeutic drugs.

Investigators at Lund University (Sweden) studied the interaction between retinoblastoma protein (RB1) and gamma-tubulin. RB1 is a tumor suppressor protein that is dysfunctional in several major cancers. One function of RB1 is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. It is also a recruiter of several chromatin-remodeling enzymes such as methylases and acetylases. RB1 belongs to the pocket protein family, whose members have a pocket for the functional binding of other proteins. In various tumors, inactivation of growth control is achieved by interfering with the RB1 signaling pathway.

Gamma-tubulin, a member of the tubulin family of proteins, is important in the nucleation and polar orientation of microtubules. It is found primarily in centrosomes and spindle pole bodies, since these are the areas of most abundant microtubule nucleation.

The investigators reported in the April 6, 2012, online edition of the Journal of Biological Chemistry that RB1 and gamma tubulin proteins moderated each other's expression by binding to their respective gene promoters. Simultaneous reduction of RB1 and gamma-tubulin protein levels resulted in an E2F1 transcription factor-dependent upregulation of apoptotic genes such as caspase 3. In various tumors types, there was an inverse correlation between the expression levels of gamma-tubulin and RB1, and that in tumor cell lines with a non-functioning RB1, reduction of gamma-tubulin protein levels led to induction of apoptosis. Thus, reduction of gamma-tubulin caused tumor cells to die while noncancerous cells survived.

“It is exciting to have research findings that are significant for several common types of cancer. This means that many patients will be affected if our work proves successful,” said senior author Dr. Maria Alvarado Kristensson, assistant professor of medical pathology at Lund University. “I judge the chances of finding a basis for a drug to be good, partly because there are already substances that block “cousins” of gamma-tubulin. If all goes well, a drug could be ready for initial tests on patients, known as “phase 1 testing,” in five to six years' time.”

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