Case Number 106042 - Methods for Diagnosing and Treating Cancers via manipulations of a non-degradative pVHL-Rpb1 ubiquitylation pathway
Contact: Kellen Sensor
Description: The novel pathway controlling RCCC tumorogenesis involves pVHL-dependent modulation of the large subunit of RNA Polymerase II, Rpb1. Low grade oxidative stress, a common pathophysiological factor in cancer, induces multiple pVHL-dependent Rpb1 modifications including P1465 hydroxylation, phosphorylation of Serine 5 within the C-terminal domain (CTD), and polyubiquitylation which does not lead to protein degradation.
RCCC cells carrying a non-hydroxylatable Rpb1 mutant (P1465) showed significantly enhanced proliferation in culture and enhanced tumoroginesis when injected into nude mice. Human RCCC tumors show alterations in Rpb1 P1465 hydroxylation, serine 5 phosphorylation and ubiquitylation. Thus, these modifications may be very useful biomarkers for detecting cancer and assessing tumor grade. In addition, the specific hydroxylases and kinases that modify Rpb1 may be effective targets for therapeutic intervention. Work is underway to identify the Rpb1 specific modulators.
A US patent application is pending.