Francois-Xavier Claret, Ph.D.
My research interests are focused on how normal and cancer cells perceive their environment by understanding how signals are received from the cell membrane (growth factors, cytokines, tumor promotors, DNA-damaging agents, and various activated oncogenes) and transmitted to the nucleus, which leads to activation of specific target genes. More specifically, my laboratory studies the abnormal activation of growth-promoting oncogenes in cancer: AP-1 (Jun/Fos oncoproteins) and its cognate Jun N-terminal kinase/stress-activated protein kinase pathway (JNK/SAPK). The Ras/Rac1/Cdc42/SEK/JNK/cJun cascade is a key pathway in cell transformation. We hope to develop a better understanding of the mechanism or mechanisms by which we can inactivate or block Ras downstream signaling targets (i.e., JNK/SAPK activation) that are overactive in many cancers. One of our study models is a mechanism of resistance to cancer chemotherapeutic agents (cisplatin, doxorubicin/daunorubicin, Taxol [paclitaxel], vincristine) in tumor cells.

A second area of interest is to link c-Jun activation by phosphorylation to apoptosis by identifying downstream targets of Jun activation. Defects in antiapoptotic signaling pathways are implicated in many pathologic conditions including cancer, in which apoptosis induced by deregulated oncogenes must be forestalled for a tumor to become established. Targeting the signal transduction pathway by inhibiting antiapoptotic signaling in cancer cells is one of our approaches.

Another major direction of my laboratory is the activation of nuclear hormone receptors (estrogen receptor [ER], glucocorticoid receptor) without assistance of a ligand through dimerization/DNA-binding/phosphorylation by mitogen-activated protein kinase (MAP kinase). Activation of these nuclear hormone receptors in cancer through the growth factor/Ras/Raf/MAPK cascade modulates the activity of AF-1 and activates their target genes. Identification of these specific kinases and elucidation of this newly identified pathway, which leads to upregulation of a transcription factor like the ER (and its cognate target genes) independent of the ligand, are under way; they may lead to new treatments for breast cancer.

As a part of the Section of Molecular Therapeutics, my research group focuses essentially on translating our new understanding of molecular mechanisms into the development of new and effective methods for treating cancer patients. These new strategies will be more specific than current chemotherapeutic drugs because they should block some of the signaling pathways that we know are inappropriately activated in many cancers.