Dr. Corinne A. Michels
Distinguished Professor of Biology
Chair of Biology Department of Queens College
Ph.D. (Columbia University)
Office: E- 102 - Tel: (718) 997- 3410
Lab: E- 101, 145 - Tel: (718) 997 - 3430
E-mail: Corinne.Michels @ qc.cuny.edu
My research uses the techniques of molecular genetic analysis to explore the mechanisms of eukaryotic gene regulation. We work with Saccharomyces cerevisiae as a model eukaryotic organism and study the MAL genes, encoding proteins required for the utilization of the sugar maltose as an example of a regulated genetic system. Maltose fermentation utilizes two enzymes, maltose permease and maltase. Synthesis of both enzymes is induced by maltose and repressed by glucose. This dual regulation is achieved via multiple mechanisms acting at the levels of transcription, protein traffiking, and protein stability.
Maltose induction is mediated by a trans-acting DNA-binding transcription activator called the MAL-activator. A major interest is the mechanism by which maltose regulates MAL-activator function. We demonstrated that the MAL-activator is a client protein of the Hsp90/Hsp70 molecular chaperone machine. Hsp90/Hsp70 chaperone is required for MAL-activator regulation and for the inducible response to maltose. MAL-activator protein co-immunoprecipitates with the chaperones Hsp90 and Hsp70 and with the co-chaperone Hop/Sti1p. Utilizing noninducible and constitutive MAL-activator mutant alleles from our collection, we demonstrated the series of chaperone complexes formed in the activation of the MAL-activator as it progresses through the Hsp90/Hsp70 chaperone cycle. Studies of co-chaperones function are underway using the MAL-activator as a model client. This work is being extended to other transcription activator clients.
Maltose permease is key to the glucose repression of MAL gene expression. Glucose reduces permease expression levels by a variety of mechanisms, including transcriptional and posttranscriptional. The MAL genes are glucose-regulated by Mig1 and Mig2 repressor. The addition of glucose to a maltose fermenting culture causes the rapid inactivation of maltose permease protein via the endocytosis and vacuolar (lysosomal) degradation. This glucose-induced inactivation is dependent upon the ubiquitination of maltose permease. We are investigating the glucose signaling pathways involved in triggering this proteolysis. Our studies suggest that a plasma membrane-localized caseine kinase 1 encoded by the essential gene pair YCK1 and YCK2 is required for activation of the transport activity of maltose permease. It is the downstream target of two glucose signaling pathways which, in response to glucose, stimulate permease internalization and proteolysis. Maltose permease phosphorylation and its role in activity and glucose-induced inactivation is under investigation.
The Saccharomyces MAL genes are a family of repeated loci that map to a region close to chromosome telomeres. Each MAL locus is a complex of three genes encoding maltose permease, maltase, and the MAL-activator. We reported on population studies of the MAL loci in a variety of Saccharomyces strains isolated from the wild and other Saccharomyces species. We are extending this genomic analysis to other disaccharide fermentation genes in other fungi species to determine whether this complex locus structure is unique to the Saccharomyces MAL genes or common to evolutionarily diverse fungi.
Genetic Techniques for Biological Research: A Case Study Approach John Wiley & Sons, Ltd., London. 2002
Resent Journal articles:
Hu, Z., Y. Yue, H. Jiang, B. Zhang, P.W. Sherwood, and C.A. Michels, 2000. Analysis of the mechanism by which glucose inhibits maltose induction of MAL gene expression in Saccharomyces. Genetics 154: 121-132.
Jiang, H. I. Medintz, P.W. Sherwood, and C.A. Michels, 2000. Metabolic signals trigger glucose-induced inactivation of maltose permease in Saccharomyces. J. Bacteriol.182: 647-654.
Medintz, I. X. Wang, T. Hradek, and C.A. Michels, 2000. A PEST-like sequence in the N-terminal cytoplasmic domain of Saccharomyces maltose permease is required for glucose-induced proteolysis and rapid inactivation of transport activity. Biochemistry 39: 4518-4526.
Jiang, H., K. Tatchell, S. Liu, and C.A. Michels, 2000. Protein phosphatase type-1 regulators REG1 and REG2 play a role in glucose-induced proteolysis of maltose permease in Saccharomyces. Molec. Gen. Genet. 263: 411-422.
Danzi, S.E., B. Zhang, and C.A. Michels, 2000. Alterations in the Saccharomyces MAL-activator cause constitutivity but can be suppressed by intragenic mutations. Curr. Genet. 294: 233-240.
Wang, X., M. Bali, I. Medintz, and C.A. Michels, 2002. Intracellular maltose is sufficient to induce MAL gene expression in Saccharomyces cerevisiae. Eukaryotic Cell 1: 696-703.
Danzi, S.E., M. Bali, and C.A. Michels, 2003. Clustered-charge to alanine-scanning mutagenesis of the Mal63 MAL-activator C-terminal regulatory domain. Curr. Genet. 44: 173-183.
Bali, M., B. Zhang, K.A. Morano, and C.A. Michels, 2003. The Hsp90 molecular chaperone complex regulates maltose induction and stability of the Saccharomyces MAL gene transcription activator Mal63p. J. Biol. Chem. 278: 47441-47448.
Wang, X. and C.A. Michels, 2004. Mutations in SIN4 and RGR1 cause consitutive expression of MAL structural genes in Saccharomyces Genetics 168: 747-757.
Gadura, N., L.C. Robinson, and C.A. Michels, 2006. Yck1,2 casein kinase type-1 signals to Glc7-Reg1 protein phosphatase to regulate the transport activity and glucose-induced inactivation of Saccharomyces maltose permease. Genetics 170: 1427-1439.
Gadura, N. and C.A. Michels, 2006. Sequences in the N-terminal cytoplasmic domain of Saccharomyces cerevisiae maltose permease are required for vacuolar degradation but not glucose-induced internalization. Curr. Genet. 50: 101-14.
List of Publications from PubMed