Peter S. Rotwein
M.D., Albert Einstein College of Medicine, 1975
Professor, Medicine
Director, Molecular Medicine Division
Joint Professor, Cell and Developmental Biology
Peptide growth factors regulate cell division, intermediary metabolism, and differentiation by binding to and activating specific cell-surface receptors, and play essential roles in the growth and development of organisms as diverse as flies, worms, frogs, and humans. Our laboratory studies the regulation and actions of the insulin-like growth factors (IGFs), peptides critical for normal embryonic and post-natal growth in mammals and other vertebrate species. One major research direction focuses on the developmental biology of the IGFs by analyzing the signal transduction pathways and effectors of IGF-mediated muscle cell survival and myoblast differentiation. These studies make use of genetic complementation of muscle cell lines engineered to lack different components of the IGF system. Our goals are to define the target genes and signaling mechanisms critical to these biological effects, which distinguish the actions of the IGFs in muscle from those of all other peptide growth factors. In recent studies we have established that IGF action promotes muscle cell survival through a pathway that involves activation of the enzymes, phosphatidylinositol-3 kinase and Akt, and the subsequent induction of the cell-cycle inhibitor, p21. We also have found that the protein phosphatase, calcineurin, collaborates with an as yet unknown IGF signaling pathway to augment muscle differentiation.
Our other major research area focuses on control of IGF gene expression by hormones and growth factors. The second messenger cAMP stimulates IGF-I gene transcription through a novel pathway mediated by the transcription factor, C/EBP delta. This activation pathway, which operates principally in osteoblasts, involves translocation of C/EBP delta from the cytoplasm to the nucleus by a post-translational mechanism that requires cAMP-dependent protein kinase (PKA), although PKA does not directly phosphorylate C/EBP delta. Our goals are to characterize this signaling pathway, to define the biochemical mechanisms by which C/EBP delta regulates IGF-I gene transcription in bone, and to determine the functions of C/EBP delta in osteoblast biology.
- Lawlor MA, Feng X, Everding D, Stewart CEH, Rotwein P. (2000) Dual control of muscle cell survival by distinct growth factor regulated signaling pathways. Mol. Cell. Biol. 20:3256-3265
- Delling U, Tureckova J, Lim HW, DeWindt LJ, Rotwein, P, Molkentin JD. (2000) A calcineurin/NFATc3-dependent pathway regulates skeletal muscle differentiation and slow myosin heavy chain expression. Mol. Cell. Biol. 20:6600-6611.
- Lawlor MA, Rotwein P. (2000) Coordinate control of muscle cell survival by distinct insulin-like growth factor activated signaling pathways. J. Cell Biol. 151:1131-1140
- Lawlor MA, Rotwein P. (2000) Insulin-like growth factor-mediated muscle cell survival: central roles for Akt and the cyclin-dependent kinase inhibitor, p21. Mol. Cell. Biol. 20:8983-8995.
- Billiard J, Umayahara Y, Wiren K, Centrella M, McCarthy TL, Rotwein, P. (2001) Regulated nuclear — cytoplasmic localization of CCAAT/Enhancer Binding Protein d in Osteoblasts. J. Biol. Chem. 276:15354-15361.
- Billiard J, Grewal SS, Lukaesko L, Stork PJS, Rotwein P.( 2001) Hormonal control of insulin-like growth factor I gene transcription in human osteoblasts: dual actions of cAMP-dependent protein kinase on CCAAT/enhancer binding protein delta. J. Biol. Chem. 276: in press.