Apoptosis as an anticancer target.

The extracellular stimulation of cells by mitogens, growth factors and hormones results in activation of phosphoinositide 3-kinase (PI3K) and generation of 3'-phosphoinositide second messengers which in turn promote cell growth, proliferation and survival via activation of phosphoinositide-dependent kinase(s) (PDKs) and the Thr/Ser kinase, Akt. Akt is a direct upstream regulator of various transcription factors and proteins known to promote cell survival and proliferation. Akt may also be involved in activation of the nutrient-dependent Thr/Ser kinase, the mammalian target of rapamycin (mTOR), itself recognized as a central controller of cell growth, a key co-regulator of growth-related protein synthesis and a specific target for G1 cell cycle arrest and growth-inhibition by the antifungal macrolid antibiotic, rapamycin. Cellular restraints on uncontrolled or excessive PI3K/PDK/Akt and mTOR signaling and cell growth and proliferation is provided by the lipid phosphatase, PTEN, which dephosphorylates the D3 phosphate of 3'-phosphoinositide lipids, thereby preventing Akt activation and subsequent growth promoting events. Constitutive de-regulation of PI3K/PDK/Akt and mTOR signaling due to mutation and/or deletion of PTEN is thought to be a major contributor to the appearance and progression of many human cancers. We are investigating the expression and/or activities of a number of key intermediates in the PI3K/PDK/Akt and mTOR signaling pathways. Affirming the predicted expression/activity relationships among key signaling intermediates may be useful in validating the relative contribution of PI3K/PDK/Akt and mTOR signaling to cancer cell growth and proliferation. Establishing a correlation between expression/activity levels of specific signaling components and cell-sensitivity to rapamycin may be useful as a diagnostic predictor(s) of rapamycin efficacy in anti-cancer chemotherapy.

Credentials

Dr. Felsted received his Ph.D. in Biochemistry from the University of California at Davis in 1969 and postdoctoral training at the University of Chicago before joining the Baltimore Cancer Research Program of the NCI in 1973. He is the recipient of supplemental NCI-Gift Funds and a supplemental NIH Intramural AIDS Targeted Antiviral Program Grant. He served on the Grant Review Committee for the American Cancer Society (1991) and as an Adjunct Faculty Member and Ph.D. Thesis Research Director for the Department of Biochemistry, George Washington University (1991-1995).

Recent Publications:

NCBI PubMed listing of publications by Ron Felsted.

Glover, C.J., Hartman, K.D., Felsted, R.L. Human N-myristoyltransferase amino-terminal domain involved in targeting the enzyme to the ribosomal subcellular fraction. J Biol Chem 272(45): 28680-9, 1997.

Turpin, J.A., Terpening, S.J., Schaeffer, C.A., Yu, G., Glover, C.J., Felsted, R.L., Sausville, E.A., Rice, W.G. Inhibitors of human immunodeficiency virus type 1 zinc fingers prevent normal processing of gag precursors and result in the release of noninfectious virus particles. J Virol 70(9): 6180-9, 1996.

Felsted, R.L., Glover, C.J., Hartman, K. Protein N-myristoylation as a chemotherapeutic target for cancer. J Natl Cancer Inst 87(21): 1571-3, 1995.

Glover, C.J., Felsted, R.L. Identification and characterization of multiple forms of bovine brain N-myristoyltransferase. J Biol Chem 29; 270(39): 23226-33, 1995.

Yu, G., Shen, F.S., Sturch, S., Aquino, A., Glazer, R.I., Felsted, R.L. Regulation of HIV-1 gag protein subcellular targeting by protein kinase C. J Biol Chem 270(9): 4792-6, 1995.