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Associate Professor of Internal Medicine
Integrative
Biology
Office: (214) 648-1405
FAX: (214) 648-1475
Email: ivor.benjamin@email.swmed.edu
The research interest of this laboratory focuses on
two major themes in mammalian stress response pathways.
Molecular Mechanisms of HSP Transcriptional Regulation
HSF1 is the major heat shock transcriptional factor that binds heat shock element (HSE) in
the promoter of heat shock proteins (HSPs) and controls rapid HSP induction in cells
subjected to various environmental stresses. To assess whether HSF1 exhibited redundant or
unique in vivo functions, we have created Hsf1 -/- deficient mice
by gene targeting. Homozygous Hsf1 -/- mice can survive to adulthood but
exhibit multiple phenotypes including: defects of the chorioallantoic placenta and
prenatal lethality; growth retardation; female infertility; elimination of the
‘classical’ heat shock response; and exaggerated proinflammatory cytokine TNF a production resulting in increased mortality after endotoxin
challenge. Interestingly, basal HSP expression is not appreciably altered by the HSF1 null
mutation suggest this factor, like the Drosophila Hsf protein, might be involved in
regulating other important genes or signaling pathways. Current strategies to establish
direct causal effects for the HSF1 transactivator include DNA microarrays to identify
novel downstream targets, and both conventional and conditional transgenesis to
characterize their functions.
Molecular Mechanisms of a B-crystallin R120G
familial cardiomyopathy
The a B- crystallin ( a BC) gene
encodes a 22 kDa heat shock protein with chaperone-like properties, which is abundantly
expressed in the lens, but in significant amounts the heart and skeletal muscle. Results
of recent genetic analysis have established that a substitution of glycine for arginine at
position 120 (Arg120Gly R120G ) in the a B-crystallin
protein causes an inheritable multisystem disorder and premature death from intractable
congestive heart failure and lethal arrhythmias. a B-crystallin R120G
cardiomyopathy is characterized by excess deposits and aggregation of a B-crystallin and intermediate filament (IF) proteins (i.e., desmin)
in cardiac cells. Individual research projects are designed to test the hypothesis that
protein misfolding and aggregate formation play pivotal roles in disease pathogenesis. Our
studies will employ transgenic and available gene knock-out models of the a B-crystallin chaperone and the heat shock transcription factors 1
and 2 ( Hsf1 and Hsf2 ). A novel feature of this approach is that it permits
studies that can test directly whether or not interventions with specific HSP chaperones
can alter the phenotype of the a B-crystallin R120G
cardiomyopathy in vivo .
Selected Publications:
Xiao X., Davis, A.A., McMillan D.R, Curry, B., Richardson, J., and Benjamin, I.J.
(1999) HSF1 is required for Extraembryonic Development, Postnatal Growth and Protection
during Inflammatory Responses in Mice. EMBO J. 18: 5943-5952
Xiao, X, and Benjamin, I.J. (1999) Stress-Responsive
Proteins in Cardiovascular Disease. Am J Hum Gen . 64: 685-690
Benjamin, I.J. and McMillan, D.R. (1998) Stress (HSP) Proteins: Molecular Chaperones in
Cardiovascular Biology and Disease. Circulation Research . 83:117-132
McMillan D.R., Xiao X., Shao L., Graves K. and Benjamin, I.J. (1998) Targeted
Disruption of Heat Shock Transcription Factor 1 Abolishes Thermotolerance and Protection
Against Heat-Inducible Apoptosis. J. Biol Chem . 273: 7523-7528
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