The Penn State team of scientists led by principal investigator Kathleen M. Mulder, Ph.D., professor of pharmacology, has found that at least 45 percent of cancer patient tumor tissues have alterations in km23.
"The alterations in km23 change the communication between km23 and other proteins in the cell," Mulder said. "The miscommunication causes traffic jams to occur among intracellular signaling proteins. Such a high frequency of km23 alterations in human tumors suggests that the alterations are important for tumor development and growth. Finding drugs to override these defects should prevent the tumor from growing and spreading further. We also hope to use the km23 alterations to diagnose specific cancers and assist physicians in identifying the best treatment for individual patients."
km23 is responsible, in part, for the movement of cellular proteins along microtubules, the "highways" of the cell. The cellular proteins, or "cargo," are actually driven along the microtubules by "motors" in the cell. One such motor is called dynein. As dynein drives along microtubules, it carries cargo from the outside of the cell toward the middle, closer to the nucleus. km23 helps to connect the right cargo to the motor so that the cargo can reach the appropriate destination. Mulder and her team also found that the process is initiated by the binding of a factor called TGFbeta to receptors on the cell''s surface. This, in turn, sends a signal to km23 telling it to attach to the motor and pick up the cargo.
This study, titled "A novel TGFbeta receptor-interacting protein that is also a light chain of the motor protein dynein," was published this week in the online version of Molecular Biology of the Cell, www.molbiolcell.org
When km23 is altered, the cargo doesn''t reach the correct destination in the cell. As a result, a traffic jam occurs and causes chaos in the cell. "So it seems that ''location, location, location'' is also critical for proteins that send signals in the cell!" Mulder said.
The initiator of the journey, TGFbeta, has been the focus of Mulder''s research program since 1988.
"TGFbeta is a critical regulator of cell growth and is present throughout the body," she said. "It is already known to play an important role in suppressing the growth of epithelial cells, the type of cell that gives rise to solid tumors. When the appropriate signals are not sent by TGFbeta, the growth of epithelial cells will not be controlled and a solid tumor can form. The alterations in km23 appear to disrupt some of the normal signals sent by TGFbeta."
Additional studies are underway that continue the analyses of km23 abnormalities in specimens from patients with ovarian, colon and breast cancer –– all solid tumors. The next step is to test drugs that would target km23 and override the defects caused by the km23 alterations in the cancer cells.
"km23 alterations in human tumor tissues may also be used as prognostic indicators to help physicians decide on the most appropriate treatment for each patient," Mulder said. "In the pharmaceutical industry, this is often referred to as ''personalized medicine,'' meaning that each patient can be checked for alterations in specific genes and their treatment targeted for the alterations specific to their cancer."
Since some of the anti-cancer drugs currently on the market are known to affect the microtubule "highways" of the cell, this research may also lead to a better understanding of precisely how and why some of the anti-cancer drugs currently in use are working.
This research was funded by the National Cancer Institute of the National Institutes of Health and, in part, by the U.S. Department of Defense.
Journal
Molecular Biology of the Cell