Small heat shock protein gene expression and function in xenopus

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Healthy cells require the synthesis and maintenance of correctly folded proteins. Environmental stresses and disease states can perturb this situation and if left unchecked could result in cell death. Small heat shock proteins (sHsps) are a class of molecular chaperones that play important roles in cellular homeostasis and protein folding as well as protecting the cell against numerous stresses including heat shock and exposure to heavy metals, reactive oxygen species and arsenite. During cellular stress, sHsps, in their role as molecular chaperones, bind to denatured protein, inhibit their aggregation, and facilitate their refolding once favorable conditions have returned. Also, sHsp synthesis or mutations have been associated with various diseases such as cancer, multiple sclerosis, various neuropathologies and muscle myopathy. Over the past 23 years, the applicant's laboratory has been actively researching sHsp gene expression and function in the model frog system, Xenopus laevis. They have made significant progress in the characterization of expression and function of the sHsp family, Hsp30. Recently, they reported on the presence and molecular chaperone function of a second Xenopus sHsp, Hsp27, a human Hsp27 homolog. The long term goals of the applicant's research program are to understand the regulation and function of Xenopus sHsps. The specific aims of this grant proposal are to: 1) analyze the mechanism(s) associated with developmental regulation of Hsp30 gene expression, 2) characterize the molecular chaperone domains of Hsp30 and Hsp27, 3) determine the effect of Hsp30 and Hsp27 depletion in heat shocked Xenopus embryos, 4) examine the effect of proteasomal inhibition on sHsp gene expression in cultured cells and embryos, and 5) characterize the effect of cadmium on Hsp30 and Hsp27 gene expression in Xenopus cultured cells and embryos. This hypothesis-driven research proposal will build on previous work and explore new areas related to sHsp gene expression and function. Knowledge regarding sHsp structure and function will provide a better understanding of various disease states.