DF/HCC Program Affiliation

Cancer Cell Biology

Research Abstract

Mitogenic/Oncogenic Signaling via Ras and the ERK-MAP kinase/RSK pathway.

The Mitogen-Activated Protein Kinases (or ERKs) and the ERK-regulated kinases (or RSKs) have been established as major participants in the regulation of cell proliferation and differentiation, but when improperly activated contribute to malignant transformation. Critical details regarding the regulation of this signaling system remain unclear. For example; what signals are responsible for the transient versus prolonged ERK/RSK activation and how does this translate into a cell context-dependent proliferation or differentiation response, what regulates the cytoplasmic and nuclear localization of these signaling enzymes, and how do these kinases regulate immediate-early gene expression? In addition, novel mitogen-regulated kinases activated downstream of the G-protein Ras are being characterized and their role in growth control investigated.


Mitogenic/Oncogenic Signaling via PI3-kinase and the p70-S6 Protein Kinase Pathway.

Together with the ERK/RSK pathway, the p70-S6 kinase signaling system is known to contribute to G1 cell cycle transition. The role of p70-S6 kinase in the regulation of protein translation and gene expression is being actively examined. A variety of signal transducing proteins have been shown to participate in p70-S6 kinase regulation. These include lipid-modifying enzymes such as phosphatidylinositol 3-kinase and PLCg, PI3-kinase-modulated kinases such as Akt/PKB, the phosphatidylinositol-like protein kinase FRAP/mTOR/RAFT, small G-proteins Cdc42 and Rac1, the proto-oncogenic exchange factors for these G proteins Dbl and TIAM-1 and the tumor suppressors, PTEN, TSC1/2, and LKB. How information from these various growth factor-regulated signal transducers and nutrient-sensing pathways converge to activate p70-S6 kinase is still unclear and is being investigated. Additional protein kinases are now being identified that participate in these signaling systems and their characterization is ongoing.


Protein Kinase Signaling Promoting Survival in Chemo-Resistant Tumor Cells.

We have completed an RNAi-based screen to identify kinases involved in promoting survival in cancer cells resistant to classical chemotherapeutics. All candidate targets are now being validated, characterized and evaluated as potential future targets for drug development.

Publications

• Holz MK, Ballif BA, Gygi SP, Blenis J.mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events.Cell 2005 Nov 18;123(4):569-80.
  16286006
• Dimitri CA, Dowdle W, MacKeigan JP, Blenis J, Murphy LO.Spatially separate docking sites on ERK2 regulate distinct signaling events in vivo.Curr Biol 2005 Jul 26;15(14):1319-24.
  16051177
• MacKeigan JP, Murphy LO, Blenis J.Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance.Nat Cell Biol 2005 Jun;7(6):591-600.
  15864305
• Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J.Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase.Proc Natl Acad Sci U S A 2004 Sep 14;101(37):13489-94.
  15342917
• Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J.Molecular interpretation of ERK signal duration by immediate early gene products.Nat Cell Biol 2002 Aug;4(8):556-64.
  12134156