A New Way to Tame an Old Oncogene
By Ingrid R Niesman & Pradipta Ghosh MD
Cells are constantly bombarded by external signals. GROW, MOVE, SYNTHESIZE; they are all regulated by incoming signals. Somehow, cells must be able to regulate the magnitudes and outcomes of these hits and still maintain a steady state of being. Researchers, lead by senior authors, Pradipta Ghosh and Marilyn Farquhar, are at the forefront of understanding some of these complex molecular mechanisms. These scientists used sophisticated molecular and microscopic methods to discover the way one particular regulatory protein - GIV/Girdin - can keep proliferative signals elicited by the oncogene, GNAS in check.
Major effectors of intracellular signaling, the G-proteins, can be inhibitory or stimulatory to signaling pathways and until recently were thought to be the control point for intracellular signal transduction. That is until a novel class of proteins – modulators of G-protein signaling – was described. These regulatory proteins can either accelerate or inhibit G-protein activation; or shutdown G proteins that are already activated - acting together to maintain signaling via G-proteins just long enough to perpetuate downstream signaling, but avoid too much for too long.
The modulator protein examined in this current study, GIV (a.k.a Girdin), is the first of its kind that can inhibit signaling via Gas proteins. GNAS, the gene that encodes Gas, is a known oncogene. Dysregulated hypersignaling via Gas is a key driver of cancers when the GNAS gene is mutated, over-expressed and/or amplified in number of cancers including McCune Albright syndrome, thyroid and parathytoid tumors, adrenocortical lesions, pituitary tumors, renal kidney tumors and, rare cases of tumors arising from autonomic ganglia, large intestine, lung and testis tumors. "What is exciting is that despite widespread consensus over the years that hyperactivation of Gas augments the oncogenic drive, the who or what keeping this drive under checks and balance in the normal epithelium was unknown" said Dr. Pradipta Ghosh, "Knowledge of how GIV inhibits Gas, and why such inhibition is critical to suppress tumor cell growth gave us a more complete understanding of the oncogenic role of the GNAS".
While it remains to be seen whether the findings here can be exploited to design strategies to inhibit oncogenic signaling via Gas, one thing is clear; this study will serve as a framework for future work and open new possibilities in both therapeutic and diagnostic realms when treating patients with abnormalities in GNAS oncogene.