Dr. Francois X. Claret
The University of Texas M. D. Anderson Cancer Center
Department of Systems Biology
- Signal transduction in cancer
- JNK/SAPK activation
- Cellular proliferation and oncogenic transformation
- JAB1 in cell cycle control and ubiquitin/proteasome signaling pathway
The CLARET LAB is a Cell Signaling and Growth Control Research Laboratory dedicated to the identification and characterization of cell-cycle regulatory pathways, signalling cascades and cell death abnormalities in the transition from a normal cell to a malignant cell. A better understanding of these mechanisms will provide the basis for the development of new cancer therapeutics, prognostic and diagnostic markers, and future chemoprevention. Our research interests are focused on understanding how signals received from the cell membrane such as growth factors, cytokines, tumor promoters, DNA-damaging agents, and various activated oncogenes, are transmitted to the nucleus resulting in changed patterns of gene expression and ultimately leading to cell growth, programmed cell death (apoptosis) or malignant transformation.
Current areas of interest include the abnormal activation of growth-promoting oncogenes in cancer: AP-1 (Jun/Fos oncoproteins) and its cognate c-Jun N-terminal protein kinase/stress-activated protein kinase pathway (JNK/p38). 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 by which we can inactivate or block Ras downstream signaling targets (e.g., JNK/p38 activation) that are overactive in many cancers.
One of our models in signaling pathway is a mechanism of resistance to cancer chemotherapeutic agents (cisplatin) in breast and ovarian cancer. We are interested in mapping the MAP kinase signaling pathways in response to chemotherapeutic drugs-induced cell death in cancer cells sensitive vs. drug-resistant. For example, we found that dysregulation in the activation of the stress pathway (JNK and p38 MAPK) leads to a downregulation of the death gene, Fas ligand, and activation of antiapoptotic signaling molecule XIAP affect the sensitivity of tumor cells to cisplatin-induced apoptosis and play a key role in the development of a chemoresistance mechanism. Linking the activation of theses MAP kinase pathways to their specific downstream subtrates/transcription factors and identifying activation of their downstream target genes with the genes-array technology is our interest. 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. We believe that investigation of the mechanisms of signal transduction and the role played by specific signaling pathways should provide potential therapeutic targets for prevention and treatment of diseases and cancer.
A second model in growth control is the studies on Jun-activation binding protein 1 (JAB1), which we identified initially as an AP-1 co-activator that promotes cell proliferation. JAB-1 also controls a critical cell cycle inhibitor p27Kip1, a protein that halts the cell-division cycle. The cyclin-dependent kinase inhibitor p27 is a potent inhibitor of the cell cycle progression, and a decrease in p27 is necessary for quiescent cells to resume division. Abnormally low amounts of p27 is an hallmark of cancer. Thus, suggesting that disruption of p27 regulatory mechanisms contributes to neoplasia. JAB1 has also been implicated recently in promoting cell proliferation by facilitating relocation of p27 activity from the nucleus to the cytoplasm, thereby accelerating p27 degradation by the ubiquitin/proteasome pathways. Recently, we have reported JAB1 overexpression in human pituitary tumors, lymphomas and breast cancer inversely associates with the cell-cycle inhibitor p27 and correlate with outcome. Validation of JAB1 as a prognostic marker, through the development of tissue microarrays (where 240 tumor tissue specimens with patient outcome are immunohistochemically analyzed on a single glass array) are our main focus in developing JAB1 as a cancer therapeutic target. These innovative approaches, through collaborative effort with pathologists and clinicians have both, the potential to improve our understanding of lymphomas, breast cancer and prostate cancer pathophysiology and also the likelihood of novel approaches to cancer therapy. We are also investigating the molecular mechanism by which JAB1 overcomes the inhibitory effect of p27 tumor suppressor on cell cycle progression, thereby facilitating cellular progression to S-phase and whether this pathway forms the molecular basis for cell proliferation and tumorigenesis. We are investigating the physiological role of JAB1 during embryogenesis and organogenesis.
Our effort to translate our new understanding of molecular mechanisms will produce more specific methods for treating cancer patients than current chemotherapeutic drugs. These new strategies should block some of the signaling pathways that we know are inappropriately activated in many cancers.
A tutorial in my laboratory would provide students with an opportunity to gain experience in molecular biology and signal transduction including: DNA/RNA isolation and purification, PCR and construction of expression vectors, mammalian cell transfections, siRNA assays, Western blot, Kinase assays and apoptosis analysis.
Claret FX, Hibi M, Dhut S, Toda T, Karin M (1996) c-Jun activation domain binding proteins (JAB1): a new group of conserved co activators that increase the specificity of AP-1 factors. Nature 383:453-7.
Mansouri A, Ridgway L, Korapati AL, Zhang Q, Tian L, Wang Y, Siddik ZH, Mills GB, Claret FX (2003) Sustained activation of JNK-p38 MAP kinase pathways in response to cisplatin leads to Fas-ligand induction and cell death in ovarian cancer cells. J Biol Chem 278:19245-56.
Kouvari MA, Rassidakis GZ, Tian L, Mansouri A, Zhang Q, Kumar R, Kittas C, Claret FX (2003) Inverse correlation between levels of JAB1 and p27Kip1 is associated with poor prognosis in breast tumors. Cancer Res 63:2977-81.
Kouvaraki MA, Korapati AL, Rassidakis GZ, Tian L, Zhang Q, Chiao P, Ho L, Evans DB, Claret FX (2006) Potential role of JAB1 as a Negative Regulator of p27kip1 in pancreatic adenocarcinoma. Cancer Research 66:8581-9.
Leventaki V, Drakos E, Medeiros LJ, Lim MS, Elenitoba-Johnson KS, Claret FX, Rassidakis GZ (2007) NPM-ALK oncogenic kinase promotes cell cycle progression through activation of JNK/c-Jun signalling in anaplastic large cell lymphoma. Blood 110:1621-30.
Tian L, Parant, JM, Leventaki V, Drakos I, Zhang Q, Parker-Thornburg J, Shackleford T, Dai, H, Lin S-Y, Lozano G, Rassidakis GZ, Claret FX. Loss of Jab1 results in failure to proliferate and spontaneous DNA damage in mice. Oncogene, #ONC-2010-00636R, Accepted, 2010
Program in Cancer Biology
Office: MDA 2SCR3-2026 (Unit 950)
Title: Associate Professor
Ph.D. - University of Lausanne - 1993