Marty W. Mayo, PhD
Role of transcription factor NF-κB in the inhibition of apoptosis
Within cells there exists a fine balance between survival and death. An early step in the progression to carcinogenesis is the ability of the cell to escape death (apoptosis). Cancer cells are able to overcome apoptotic pathways by upregulating gene products that inactivate the cell death machinery. The Mayo group was among the first to describe the involvement of the transcription factor NF-?B in this inhibition of apoptosis. Classic NF-?B, composed of a p50/p65 heterodimer protein complex, is ubiquitously expressed in cells. The activation of NF-?B stimulates the production of gene products that protect cells from apoptosis, a process that directly impacts cancer progression. NF-?B is activated in response to chemotherapy and irradiation, an effect that blunts the effectiveness of these anti-cancer treatments. Clearly, an important topic in cancer research today is to understand how NF-?B becomes dysregulated in transformed cells. The laboratory is broadly interested in identifying key regulatory molecules that control NF-?B-dependent transcription at the chromatin level. Two ongoing research objectives are: 1) to understand how serine kinases lead to dysregulated NF-?B transcription and cell survival by their ability to phosphorylate and inactivate corepressor complexes on chromatin, and 2) to identify coactivators (acetyltransferases) and co-repressors (deacetylases) that modulate the transcription potential of NF-?B.
The laboratory is collaborating with Dr. Jeff Smith evaluating the role of the NAD-dependent deacetylases on NF-kB transcription and deacetylation of novel signaling molecules. Moreover, they collaborate with Dr. David Jones, a thoracic surgeon interested in the anti-apoptotic role of NF-kB in lung cancer. The collaborative efforts have shown that the ineffectiveness of HDAC inhibitors to induce apoptosis in non-small cell lung cancer (NSCLC) tumors is due, in part, to the fact that these agents activate NF-kB-dependent cell survival pathways. Thus, inhibition of NF-kB greatly sensitizes NSCLC tumors to anti-cancer therapy involving HDAC inhibitors. Based on their interests in cancer prevention they have formed a translational research and development team for initiating drug trials on lung cancer patients. This group is composed of Dr. Heidi Gillenwater (Hematology/Oncologist), David Jones and Dr. Mayo. The efforts are to implement translational research discoveries from the laboratory to the patient's bedside.