Liz's Science Page

    Programmed cell death is a necessary developmental phenomenon that is widespread in the nervous system.  Evidence accumulated using a well characterized model for programmed cell death has led to the hypothesis that neurotrophic factor-deprivation induced death is mediated in part by proteins encoded by specific genes that increase in expression after trophic factor withdrawal (see Fig. 1 below).  The focus of my thesis project is to characterize a gene called SM-20 that was identified in our laboratory by differential display as a gene that increases in expression in sympathetic neurons during nerve growth factor (NGF)-deprivation induced death.  Data indicate that expression of SM-20 protein in neurons is sufficient to induce cell death in the presence of NGF.  SM-20 has been independently identified as an immediate-early gene in smooth muscle cells (Wax et al., 1994) and as a gene expressed in fibroblasts following activation of the p53 protein (Madden et al., 1996), an event leading to growth-arrest and apoptosis.  My thesis proposal will assess the hypothesis that SM-20 plays a functionally significant role in neuronal death by characterizing the death induced by SM-20 overexpression and by determining the effects of inhibiting SM-20 function on NGF-deprivation induced death.  These studies will determine the significance of SM-20 for neuronal death caused by trophic factor withdrawal and will help to characterize the function of this novel protein in the nervous system.

Click to see the full size diagram

Fig. 1.  Sequence of events during cell death after NGF deprivation of SCG neurons.  Shown are inhibitors of neuronal apoptosis (TOP) and parameters that increase (MIDDLE: e.g., ROS, c-Jun, cyclin D1, SM-20) and decrease (BOTTOM: e.g., total RNA and protein synthesis) during neuronal death.  The relative sites of action of inhibitors of cell death have not all been confirmed but are placed based upon our interpretation of the available data.  ROS, reactive oxygen species; CHX, cycloheximide; ActD, actinomycinD.

Selected References

Martin, D.P., Schmidt, R.E., DiStefano, P.S., Lowry, O.H., Carter, J.G., and Johnson, E.M., Jr. Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation.  J. Cell Biol. 106:829-844, 1988.

Clarke, P.G. Developmental cell death: morphological diversity and multiple mechanisms.  Anat. Embryol. (Berl.) 181:195-213, 1990.

Deckwerth, T.L. and Johnson, E.M., Jr. Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor (NGF).  J. Cell Biol. 123:1207-1222, 1993.

Wax, S.D., Rosenfield, C.L., and Taubman, M.B. Identification of a novel growth factor responsive gene in vascular smooth muscle cells.  J. Biol. Chem. 269:13041-13047, 1994.

Madden, S.L., Galella, E.A., Riley, D., Bertelsen, A.H., and Beaudry, G.A. Induction of cell growth regulatory genes by p53.  Cancer Res. 56:5384-5390, 1996.

Deshmukh, M. and Johnson, E.M., Jr. Programmed cell death in neurons: focus on the pathway of nerve growth factor deprivation-induced death of sympathetic neurons.  Mol. Pharmacol. 51:897-906, 1997.

Lipscomb, E.A., Sarmiere, P.D., Crowder, R.J., and Freeman, R.S.  Expression of the SM-20 gene promotes death in nerve growth factor-dependent sympathetic neurons.  J. Neurochem. 73:429-432, 1999.

Elizabeth Lipscomb
Ph.D. Candidate, Toxicology Training Program
Department of Environmental Medicine
601 Elmwood Ave. Box EHSC
Rochester, NY 14642

Last updated July 15, 2002