Roya KhosraviFar Lab
Normal development of multicellular organisms is controlled by a delicate balance between signals that regulate cell proliferation, differentiation and programmed cell death. Deregulation of any of these cellular process leads to a variety of human diseases, including cancer. A major interest of our laboratory is elucidating the mechanism by which oncogenes promote evasion of tumor cells from apoptosis. In addition, we are investigating the signal transduction pathways that regulate cell fate, in particular ones that are involved in mediating apoptosis by members of TNF family of ligand. Selected examples of our current projects are described briefly:
1) A crucial aspect of tumorigenesis is the evasion of apoptosis. An understanding of how oncogenes cause resistance to apoptosis will help in the design of more suitable anti-cancer therapies, yet, the mechanisms by which some of the most prominent oncogenes, such as BCR-ABL enable protection from apoptosis are far from clear. Recently, we have observed that BCR-ABL induces evasion of transformed cells from apoptosis by downregulating the transcription of many pro-apoptotic factors. We are currently investigating the molecular mechanism by which BCR-ABL regulates the transcription and expression of these pro-apoptotic genes.
2) Recent discovery of TNF-related apoptosis inducing ligand, TRAIL, that selectively induces apoptosis of transformed cells in vitro, has provided hope for the use of TRAIL as a cancer therapeutic. However, the signaling events that mediate the biological effects of TRAIL and its receptors are not well characterized. Recently, we have identified several proteins that specifically interact with TRAIL receptors. We are characterizing these proteins and have found that one of them specifically interacts with TRAIL-R2 in a ligand-independent manner to prevent spontaneous death signaling. We are currently investigating the mechanism of function of this and other death receptor interacting molecules.
3) Death receptors initiate ubiquitous pathways of cell death in which caspase activation is mediated either directly without mitochondrial amplification or via the release of apoptogenic factors from mitochondria. We have recently observed that death receptor signaling induces alteration in mitochondrial membrane lipids independently of caspase activation, thus facilitating the action of pro-apoptotic proteins in releasing apoptogenic factors through a PI-3K-dependent pathway. We are currently investigating the molecular mechanism for the caspase-independent regulation of the mitochondrial death pathway.