Department of Biochemistry
School of Medicine & Biomedical Sciences
Faculty

The Roles of Protein Methylation in Growth and Differentiation

PC12 cells extend long, branched neurites when exposed to nerve growth factor (NGF). We recently found that NGF stimulates the methylation of several proteins in these cells and that methylation is essential for neurite outgrowth. Among the proteins methylated in response to NGF and inhibited when neurite outgrowth is ablated are several RNA-binding proteins that regulate gene expression by affecting RNA processing, and mRNA nucleocytoplasmic transport, half life or translation. Our goal is to determine the roles of these proteins in nerve cell differentiation and exactly how methylation affects these functions.

Yeast (Saccharomyces cerevisiae) cultures are being used to study the role of protein methylation in growth. The approach was to construct a disruption mutant of S-adenosylhomocysteine hydrolase (SAHH), an enzyme required for normal methylation. The mutant exhibits remarkably abnormal growth. While log-phase growth normally begins after about a 12 hour lag, the lag phase for the mutant is 4-6 days and growth stops at approximately 1/6 the total number of cells as wild type! Total protein methylation is 40-fold less in the mutant. The goals are to identify the proteins whose methylations are required for normal growth, their functions in growth, and how methylation is required for those functions.

Selected Recent Publications

Aletta, J.M., Cimato, T.R. and Ettinger, M.J. (1998) Protein methylation: a signal event in post-translational modification. TIBS 23: 89-91.

Cimato, T.R., Ettinger, M.J., Zhou, X.B. and Aletta, J.M. (1997) Nerve growth factor-specific regulation of protein methylation during neuronal differentiation of PC12 cells. J. Cell Biol. 138: 1089-1103.

Petrovic, N., Comi, A. and Ettinger, M.J. (1996) Copper incorporation into superoxide dismutase in Menkes lymphoblasts. J. Biol. Chem. 271: 28335-28340.

Petrovic, N., Comi, A. and Ettinger, M.J. (1996) Identification of an apo-superoxide dismutase (Cu/Zn) pool in human lymphoblasts. J. Biol. Chem. 271: 28331-28334.

Bethin, K.E., Petrovic, N. and Ettinger, M.J. (1995) Identification of a major hepatic copper protein as S-adenosylhomocysteine hydrolase. J. Biol. Chem. 270: 20698-20702.

Bethin, K.E., Cimato, T.R. and Ettinger, M.J. (1995) Copper binding properties and the effects of abnormal copper status on the levels of S-adenosylhomocysteine hydrolase. J. Biol. Chem. 270: 20703-20711.

Seo, H.C. and Ettinger, M.J. (1993) Identification and purification of a self-associating, copper-binding protein from mouse hepatic cytosols. J. Biol. Chem. 268: 1151-1159.

Seo, H.C. and Ettinger, M.J. (1993) Purification and properties of a self-associating, 50-kDa copper-binding protein from brindled mouse livers. J. Biol. Chem. 268: 1160-1165.

Palida, F. and Ettinger, M.J. (1991) Identification of proteins involved in intracellular copper metabolism. Low levels of a 48-kDa copper-binding protein in the brindled mouse model of Menkes disease. J. Biol. Chem. 266: 4586-4592.

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