Khokhlatchev, Andrei
Primary Appointment
Senior Scientist, Hematology and Oncology
Contact Information
Box 800214
Email: ak9k@virginia.edu
Research Interests
Molecular Mechanisms of Tumor Suppression by NORE1A family of Proteins
Research Description
Our laboratory is interested in Ras signal transduction and the molecular mechanisms
of tumor suppression, specifically within the novel family of tumor suppressors
represented by NORE1 and RASSF1. In humans, Ras is the most common dominant oncogene,
frequently activated by mutation. Ras activation often leads to uncontrolled cell
proliferation and tumor development. Therefore, it is likely that there are molecular
mechanisms in cells that sense the suitability of Ras activation, and in the case
of inappropriate activation, blocks cell proliferation or eliminate the cell.
NORE1 was discovered as a protein capable of binding to activated Ras in vitro
and in vivo with high affinity. Data obtained by us and others suggests that
NORE1, specifically its longest splice isoform NORE1A, is a tumor suppressor,
affected in lung, breast, colorectal, kidney and other cancers. Our hypothesis
is that NORE1 is the key regulator in Ras signaling, determining an outcome
of proliferation or cell cycle arrest or apoptosis. Currently, we are focused
on structure-functional studies of NORE1A to determine and characterize regions
of the molecule essential for growth and tumor suppression, studying mechanism
of NORE1A activation by Ras and identifying components of growth-inhibitory
signal transduction pathway that starts at NORE1A.
RASSF1 is located on human chromosome 3p21, among a cluster of putative tumor
suppressor genes. This cluster is frequently deleted in lung tumors, as well
as in many breast, renal, hepatic, prostate, head/neck and other cancers. Forced
expression of the RASSF1A gene in such tumor cell lines substantially suppresses
their growth rate in vitro and in vivo. RASSF1 is closely related to NORE1;
however, RASSF1 cannot bind Ras. To understand the mechanism of RASSF1A tumor
suppression, we are going to investigate how this protein is activated, specifically
at what conditions it is capable to bind Ras.