Dr. George Molloy

Associate Professor

Contact

Molloy

Office: 231 McKinly Lab

Mailing address:
Department of Biological Sciences
Wolf Hall
University of Delaware
Newark, DE 19716

Phone: (302) 831-8478
Fax: (302) 831-2281
E-mail: gmolloy@udel.edu

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Education

B.S.: Manhattan College
Ph.D.: Virginia Polytechnic Institute
Postdoctoral: Columbia University
Postdoctoral: Rockefeller University

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Research Interests

Current interest is in (i) control of transcription of the rat brain creatine kinase (CKB) gene in neurons and glial cells (i.e. oligodendrocytes and astrocytes) during postnatal rat brain development; (ii) control of transcription of CKB mRNA during embryonic development; (iii) the physiological role and regulated subcellular localization of the CKB protein in differentiated astrocytes and oligodendrocytes. The above are important since creatine kinase (CK) is a metabolic enzyme involved in maintenance of high ATP levels in cells where energy requirements are high (e.g. glial and neuronal cells). Knowledge of how the cell controls the transcription of CKB mRNA is important since it will help explain how the cell controls transcription of genes which are activated during the differentiation of glial and neuronal cells and, possibly, how cells respond when ATP levels become low. CKB mRNA transcription is high in brain oligodendrocytes and astrocytes and some neurons in the cerebellum but appears to be repressed in a number of other tissues (e.g. adult liver). Therefore, we are interested in defining the cis-acting CKB promoter sequences and trans-acting nuclear factors regulating CKB transcription. Studies on the expression of rat CKB during brain development represent an attractive experimental system because: (1) The CKB gene has been cloned and sequenced and the enzymatic function of the CKB enzyme is well understood - CKB regenerates ATP; (2) The expression and function of CKB during the differentiation of brain oligondendrocytes, astrocytes and neurons can be readily studied since astrocytes and oligodendrocytes and their precursors can be isolated from rat brain and their differentiation can be followed relatively easily using in vitro tissue culture; (3) CKB is a small gene (2.5 kb) which is present in one copy per haploid genome and CKB mRNA does not undergo alternative splicing - therefore, the expression pattern of CKB is relatively straightforward; this will facilitate examining expression of the CKB gene in transgenic mice; (4) CKB is relevant to a number of disease situations: (i) Multiple Schlerosis: a demyelinating disease. CKB plays an important in regenerating ATP to allow myelination to occur in oligodendrocytes. (ii) Ischemia and hypoxia: injuries to cells resulting in depletion of ATP. CKB appears to be elevated in early phases of ischemia and hypoxia in an attempt to regenerate ATP.

More about Dr. Molloy's research...

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Current Projects

• Differences in the timing and regulation of CKB transcription during postnatal development of rat brain cerebellum and cerebrum - Identification of the important CKB promoter elements and nuclear transcription factors.
• Regulation of CKB expression during embryonic development - Use various CKB promoter constructs introduced into transgenic mice to measure expression of CKB mRNA in various tissues during embryonic development. This will establish the timing of CKB expression in different embryonic tissues and provide the framework to identify the CKB gene regulatory DNA elements responsible for expression.
• Mechanism by which cAMP activates CKB transcription - In U87-MG glioblastoma cells, elevated cAMP activates CKB transcription via a pathway involving protein kinase A and the transcription factor AP-2. Under investigation are: (i) the involvement of any other factors and (ii) whether cAMP activates CKB transcription in any regions of rat brain.
• CKB protein is present in the cytoplasm and nucleus of immature oligondendrocytes but only in the cytoplasm of differentiated oligondendrocytes - Determine what regulates this subcellular localization of CKB protein in oligondendrocytes.

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Teaching

• BISC 103 - Principles of Biology
• BISC 104* - Principles of Biology with Lab
• BISC 602 - Molecular Biology of Animal Cells
• BISC 667 - Molecular Neurobiology

*Course web site available through MyCourses

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Research Group

• Dianna Willis, B.S. - (Graduate Student) Regulation of CKB transcription by cAMP in U87-MG glioblastoma cells and during postnatal brain development.
• Wei Shen, B.S. - (Graduate Student) Regulation of CKB expression during postnatal brain development in the cerebrum and cerebellum.

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Selected Publications

Willis, D., Zhang, Y., and Molloy, G.R. (2005) Transcription of brain creatine kinase in U87-MG glioblastoma is modulated by factor AP2. Biochim. Biophys. Acta. 1728: 18-33.

Shen, W., Willis, D., Zhang, Y., and Molloy, G.R. (2003) Expression of creatine kinase isoenzyme genes during postnatal development of rat brain cerebrum: Evidence for posttranscriptional regulation. Dev. Neurosci. 25: 421-435.

Shen, W., Willis, D., Zhang, Y., Schlattner, U., Walliman, T., and Molloy, G.R. (2002) Expression of creatine kinase isoenzyme genes during postnatal development of rat brain cerebellum: Evidence for transcriptional regulation. Biochem. J. 367: 369-380.

Willis, D., Parameswaran, B., Shen, W. and Molloy, G.R. (1999) Conditions providing enhanced transfection efficiency in rat pheochromocytoma PC12 cells permit analysis of the activity of the far-upstream and proximal promoter of the brain creatine kinase gene. J. Neuroscience Methods 92: 3-13.

Kuzhikandathil. E. and Molloy, G.R. (1999) The proximal promoter of the rat brain creatine kinase gene lacks a concensus CRE element but is essential for the cAMP-mediated increased transcription in glioblastoma cells. J. Neroscience Res. 56: 371-385.

Wilson, C.D., Shen, W., and G.R. Molloy (1997) Expression of the brain creatine kinase gene is low in neuroblastoma cells. Dev. Neurosci. 19: 375-383.

Wilson, C.D., Shen, W., Kuzhikandathil, E. and G.R. Molloy (1997) Expression of the brain creatine kinase gene in rat RT4 neurotumor cells and its modulation by cell confluence. Dev. Neurosci. 19: 384-394.

Zhao, J., Schmieg, F., Dodgson, N., Simmons, D.T. and Molloy, G.R. (1996) p53 binds to a novel recognition sequence in the proximal promoter of the rat muscle creatine kinase gene and activates its transcription. Oncogene 13: 293-302.

Ilyin, S.E., Plata-Salamon, C.R., Molloy, G.R., Sonti, G. (1996) Creatine Kinase B mRNA levels in brain regions from male and female rats. Molecular Brain Research 41: 50-56.

Kuzhikandathil, E., and Molloy, G.R. (1995) Prostaglandin E1 and E2 and Cholera toxin increase transcription of the rat brain creatine kinase gene in the human U87 glioblastoma cell line. GLIA 15: 471-479.

Zhao, J., Schmieg, F., Simmons, D.T. and Molloy, G.R. (1994) Mouse p53 represses the rat brain creatine kinase gene but activates the rat muscle creatine kinase gene. Mol. Cell. Biol. 14: 8483-8492.

Kuzikanithil, E., and Molloy, G.R. (1994) Transcription of the rat brain creatine kinase gene in glial cells is modulated by cAMP-dependent protein kinase. J. Neuroscience Res. 39: 70-82.

Wilson, C.D., Parameswaran, B. and Molloy, G.R. (1993) Expression of the brain creatine kinase gene in rat C6 glial cells. J. Neuroscience Research 35: 92-102.

Molloy, G.R., C.D. Wilson, P. Benfield, J. deVellis and S. Kumar (1992) Expression of the rat brain creatine kinase gene is high in primary astrocytes and oligodendrocytes and low in neurons. J. Neurochemistry 59: 1925-1932.

Hobson, G.M., Molloy, G.R., and Benfield, P.A. (1990) Identification of cis-acting regulatory elements in the promoter region of the rat brain creatine kinase gene. Mol. Cell. Biol. 10: 6533-6543.

Hobson, G.M., Mitchell, M.T., Molloy, G.R., Pearson, M.L. and Benfield, P.A. (1988) Identification of a novel TA-rich DNA binding protein that recognizes a TATA sequence within the brain creatine kinase promoter. Nucleic Acids Research 16: 8925-8944.

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