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Thomas Jefferson University - Edward Winter, PhD
Edward Winter, PhD

Biochemistry & Molecular Biology
Thomas Jefferson University
Jefferson Medical College
Department of Biochemistry & Molecular Biology
Professor

Mailing Address
233 South 10th Street, 228 BLSB
Philadelphia, Pennsylvania 19107
United States
Contact Information
Phone: (215) 503-4139
Fax: (215) 503-9162
Edward.Winter@jefferson.edu
Qualifications
Ph.D. (1985) State University of New York at Stony Brook

Expertise and Research Interests
Defects in meiotic regulation are a significant cause of infertility, birth defects, spontaneous abortion, and disease. The Winter laboratory studies mechanisms that regulate meiotic development using the yeast Saccharomyces cerevisiae as a model system. Our current work is focused on two major areas of investigation

1- The transcriptional cascade of meiosis. Transcriptional cascades are ubiquitous in biological systems. They play a particularly prominent role in controlling cellular differentiation programs. The transcriptional program of meiosis consists of 3 major sets of genes termed early, middle and late. Early genes are involved in meiotic S-phase, homolog pairing, synaptonemal complex formation, and genetic recombination. Middle genes control the nuclear divisions and gametogenesis (spore formation). Late genes control spore maturation. These 3 sets of genes are further temporally diversified to yield as many as 12 subsets that are expressed as different steps in the program are taking place. The induction of middle genes controls exit from meiotic prophase. In yeast, this transition corresponds to the commitment point, after which the inducing signal is no longer needed to complete the program. Middle promoters are controlled by a repressor protein (Sum1), that recruits a sirtuin (Hst1). In addition, a transcriptional activator (Ndt80) acts in opposition to Sum1/Hst1. Sum1 and Ndt80 compete for binding to overlapping DNA elements (termed middle sporulation elements or MSEs) and NDT80 expression is controlled by an MSE in its own promoter. These interactions form a transcriptional switch that triggers meiotic chromosome segregation, meiotic commitment, and completion of the program. This transcriptional switch is regulated by dependency and checkpoint signals. Feed-forward interactions give switch-like properties to the system. We are currently using molecular genetic approaches to define the signals that control the Sum1/Ndt80 switch and elucidate how this switch regulates meiotic progression.

2- Meiosis-specific signaling networks. A large fraction of the genes that are regulated by the transcriptional program of meiosis encode signaling molecules. The transient expression of different sets of signaling molecules allows a single cell to respond to different nutritional, cell-cycle, and dependency signals as different steps in the program are taking place. We previously described a meiosis-specific signaling network that controls multiple steps in meiotic development. Key members of this signaling network include a meiosis-specific cyclin-dependent kinase (CDK) -like kinase that superimposes meiotic regulation at multiple steps in the program (Ime2), a meiosis-specific MAPK that is uniquely required for the post-meiotic program of spore formation (Smk1), the CDK activating kinase (Cak1) that activates both Ime2 and Smk1, and a meiosis-specific targeting subunit for the anaphase-promoting complex E3 ubiquitin-ligase (Ama1). We are currently investigating how Smk1 is regulated to elucidate how meiosis is coupled to gamete formation and how the Ime2 CDK-like kinase superimposes meiotic regulation on the mitotic default pathway.


Laboratory Staff
Keywords
Biological Sciences; Map Kinase; Meiosis; Microbial Genetics; Sporulation; Yeast
Publications
  • Shin, M.E., Skokotas, A., and E. Winter The Cdk1 and Ime2 protein kinases trigger exit from meiotic prophase in Saccharomyces cerevisiae by inhibiting the Sum1 transcriptional repressor. Mol. Cell. Biol. 30(12):2996-3003, Jun 2010.
  • Ahmed, N., Bungard, D., Shin, M.E., Moore, M., and E. Winter. The Ime2 CDK-like Kinase Enhances the Disassociation of the Sum1 Repressor from Middle Meiotic Promoters. Mol. Cell. Biol. 29(16):4352-4362, Aug 2009.
  • McDonald, C.M., Wagner, M., Dunham, M.J., Shin, M.E., Ahmed, N.T., and E. Winter. The Ras/cAMP pathway and the CDK-like kinase Ime2 regulate the MAPK Smk1 and spore morphogenesis in S. cerevisiae. Genetics 181(2):511-23, Feb 2009.
  • Moore, M., Shin, M.E., Bruning, A., Schindler, K., Vershon, A., and E. Winter. Arg-Pro-X-Ser/Thr-Ala is a Consensus Phosphoacceptor Sequence for the Meiosis-Specific Ime2 Protein Kinase in Saccharomyces cerevisiae. Biochemistry 46(1):271-8, Jan 2007.
  • Krishnamoorthy T., Chen X., Govin J., Cheung W.L., Dorsey J., Schindler K., Winter E., Allis C.D., Guacci V., Khochbin S., Fuller M.T., and S.L. Berger. Phosphorylation of histone H4 Ser1 regulates sporulation in yeast and is conserved in fly and mouse spermatogenesis. Genes and Development 20(18):2580-92, Sep 2006.
  • Schindler, K., and E. Winter. Phosphorylation of Ime2 regulates meiotic progression in Saccharomyces cerevisiae. Journal of Biological Chemistry 281(27):18307-16, Jul 2006.
  • McDonald, C.M., Cooper, K.F., and E. Winter. The Ama1-directed anaphase-promoting complex regulates the Smk1 mitogen-activated protein kinase during meiosis in yeast. Genetics 171(11):901-911, Nov 2005.
  • Bungard, D., Reed, M., and E. Winter. RSC1 and RSC2 are required for the expression of mid-late sporulation-specific genes in Saccharomyces cerevisiae. Eukaryotic Cell 3(4):910-918, Aug 2004.
  • Schindler, K., Benjamin, K.S., Martin, A., Boglioli, A., Herskowitz, I., and Winter, E. The Cdk-activating kinase Cak1 promotes meiotic S-phase through Ime2p. Molecular and Cellular Biology 23(23):8718-8728, Dec 2003.
  • Pierce, M., Benjamin, K.R., Montano, S.P., Georgiadis, M., M., Winter, E., and Vershon, A.K. Sum1 and Ndt80 proteins compete for binding to MSE sequences that control meiotic gene expression. Molecular and Cellular Biology 23(14):4814-4825, July 2003.
  • Schaber, M., Lindgren, A., Schindler, K., Bungard, D., Kaldis, P., and E. Winter. Cak1 promotes meiosis and spore formation in Saccharomyces cerevisiae in a Cdc28-independent fashion. Molecular and Cellular Biology 22(23):57-68, Jan 2002.
  • Kaldis, P., Tsakraklides, V., Ross, K., Winter, E., and A. Cheng The CDK-Activating Kinase, edited by Philipp Kaldis, Eurekah Press 2001.
  • Lindgren, A., Bungard, D., Pierce, M., Xie, J., Vershon, A., and Winter, E. (2000) The pachytene checkpoint in Saccharomyces cerevisiae requires the Sum1 transcriptional repressor. The EMBO Journal. 19(23):6489-6497, Dec 2000.
  • Xie J, Pierce M, Gailus-Durner V, Wagner M, Winter E, Vershon AK. Sum1 and Hst1 repress middle sporulation-specific gene expression during mitosis in Saccharomyces cerevisiae. EMBO Journal. 18(22):6448-54, Nov 1999.
  • Wagner M, Briza P, Pierce M, Winter E. Distinct steps in yeast spore morphogenesis require distinct SMK1 MAP kinase thresholds. Genetics. 151(4):1327-40, Apr 1999.
  • Kaldis P, Pitluk ZW, Bany IA, Enke DA, Wagner M, Winter E, Solomon MJ. Localization and regulation of the cdk-activating kinase (Cak1p) from budding yeast. Journal of Cell Science. 111:3585-96, Dec 1998.
  • Pierce M, Wagner M, Xie J, Gailus-Durner V, Six J, Vershon AK, Winter E. Transcriptional regulation of the SMK1 mitogen-activated protein kinase gene during meiotic development in Saccharomyces cerevisiae. Molecular and Cellular Biology. 18(10):5970-80, Oct 1998.
  • Wagner M, Pierce M, Winter E. The CDK-activating kinase CAK1 can dosage suppress sporulation defects of smk1 MAP kinase mutants and is required for spore wall morphogenesis in Saccharomyces cerevisiae. EMBO Journal. 16(6):1305-17, Mar 1997.
  • Hall JP, Cherkasova V, Elion E, Gustin MC, Winter E. The osmoregulatory pathway represses mating pathway activity in Saccharomyces cerevisiae: isolation of a FUS3 mutant that is insensitive to the repression mechanism. Molecular and Cellular Biology. 16(12):6715-23, Dec 1996.
  • Reardon BJ, Gordon D, Ballard MJ, Winter E. DNA binding properties of the Saccharomyces cerevisiae DAT1 gene product. Nucleic Acids Research. 23(23):4900-6, Dec 1995.
  • Krisak L, Strich R, Winters RS, Hall JP, Mallory MJ, Kreitzer D, Tuan RS, Winter E. SMK1, a developmentally regulated MAP kinase, is required for spore wall assembly in Saccharomyces cerevisiae. Genes and Development. 8(18):2151-61, Sep 1994.
  • Reardon BJ, Winters RS, Gordon D, Winter E. A peptide motif that recognizes A.T tracts in DNA. Proceedings of the National Academy of Sciences (USA). 90(23):11327-31, Dec 1993.
  • Brewster JL, de Valoir T, Dwyer ND, Winter E, Gustin MC. An osmosensing signal transduction pathway in yeast. Science. 259(5102):1760-3, Mar 1993.
  • Zhang, S., Lockshin, C., Herbert, A., Winter, E., and Rich A. Zoutin, a Z-DNA binding protein in Saccharomyces cerevisiae. The EMBO Journal, 11:3787-3796, 1992.
  • Ballard, M.J., Tyndall, W.A., Shingle, J.M., Hall, D., and E. Winter. Tyrosine phosphorylation of a yeast 40 kDa protein occurs in response to mating pheromone. The EMBO Journal:10, 3753-3758, 1991.
  • Winter, E. and Varshavsky, A. A DNA binding protein that recognizes oligo(dA).oligo(dT) tracts. The EMBO Journal 8:1867-1877, 1989.
  • Kahn, S., Yamamoto, F., Almoguera, C., Winter, E., Forrester, K., Jordano, J. and Perucho, M. The c-K-ras gene and human cancer. Anticancer Research 7:639-652, 1987.
  • Winter, E. and Perucho, M. Oncogene amplification during tumorogenesis of established rat fibroblasts reversibly transformed by activated human ras oncogenes. Mol. Cell Biol. 6:2562-2570, 1986.
  • Winter, E., Yamamoto, F., Almoguera, C. and Perucho, M. A method to detect and characterize point mutations in transcribed genes: Amplification and overexpression of the mutant c-Ki-ras allele in human tumor cells. Proc. Natl. Acad. Sci. USA 82:7575-7579, 1985.
  • Winter, E., Levy, D. and Gordon J.S. Changes in the H-1 histone complement during myogenesis. I. Establishment by differential coupling of H-1 species synthesis to DNA replication. J. Cell Biol. 101:167-174, 1985.
  • Winter, E., Palatnik, C.M., Williams, D.L., Coles, L.S., Wells, J.R.E. and Gordon, J.S. Changes in the H-1 histone complement during myogenesis. II. Regulation by differential coupling of H-1 variant mRNA accumulation to DNA replication. J. Cell Biol. 101:175-181, 1985.

Individual Expertise profile of Edward Winter, PhD, Copyright © Edward Winter, PhD.
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