We wish to understand the molecular basis of signal transduction in normal and cancer cells.
Mitogenic/Oncogenic Signaling via Ras and the ERK-MAP kinase/RSK pathway.
Activation of the proto-oncoprotein Ras, results in activation of the Mitogen-Activated Protein Kinases (or ERK-MAPKs) and the ERK-regulated kinases (or RSKs). When improperly regulated, ERK and RSK contribute to a variety of human diseases, including cancer. We are utilizing a variety of biochemical, cell biological and RNAi-based approaches to identify new ERK and RSK targets and how they contribute to the regulation of immediate-early gene expression, cell motility, cell proliferation, differentiation, and/or cell survival. We are also deterrmining how temporal regulation and spatial distribution of ERK and RSK translates into a cell context-specific response. How this G0/G1 signaling system communicates with the G1 cell cycle machinery is also being investigated.
Mitogenic/Oncogenic Signaling via PI3-kinase and the p70-S6 protein kinase pathway.
Phosphatidylinositol 3-kinase (PI3K) signaling regulates protein translation, cell size/growth, G1 cell cycle progression, and cell survival. PI3K is activated by a variety of growth factors and cytokines and is constitutively activated by loss of function of the tumor suppressor PTEN, which occurs in greater than 30% of human cancers. The molecular basis of S6K and eIF4E activation and signaling, two major PI3K effectors, their role in mRNA processing/translation and ribosome biogenesis, and their contribution to tumorigenesis is a focus or our work.
Integration of signaling by nutrients, energy sufficiency and growth factors.
Nutrient/energy signaling pathways converge upon mitogen-regulated signaling pathways to regulate various critical biological processes. Tumor suppressors mutated in diseases such as tuberous sclerosis (TSC1/2) or Peutz-Jeghers syndrome (LKB1) regulate signaling to the nutrient sensor mTOR. mTOR is specifically inhibited by the drug rapamycin, an FDA-approved immunosuppressant and inhibitor of restenosis. Rapamycin is also currently in clinical trials for a variety of cancers. How nutrients, energy sufficiency or cell stress signal to mTOR, and how mitogenic signals and nutrient/energy signals collaborate to regulate S6 kinases and eIF4E is under investigation.
Identification and characterization of novel kinases/phosphatases involved in carcinogenesis.
Evasion from apoptosis is a hallmark of cancer. We have utilized RNA interference (RNAi) to systematically screen the kinase and phosphatase component of the human genome. We have identified several new survival kinases. phosphatases and associated regulatory subunits that promote cell survival. We also identified novel phosphatases with tumor suppressor-like activity. Finally, RNAi targeting of specific kinases sensitizes resistant cells to chemotherapeutic agents. We are currently characterizing many of these novel enzymes.
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