The ability of malignant cells to survive and eventually develop resistance to the cytotoxic agents used for their eradication is a major obstacle to the successful treatment of cancer. If the mechanisms underlying the ability to survive lethal stresses were understood they could potentially be manipulated resulting in the successful treatment of cancer. The long term goal of this proposal is to understand the molecular mechanism(s) whereby the expression of a specific heat shock protein, hsp27 protects cells from lethal stresses, and to determine if this protection can occur in vivo. In order to achieve this goal, mutated forms of hsp27 will be constructed, inserted into expression vectors and transfected into mammalian cell lines. The subcellular location and ability to increase cellular resistance to stresses will be evaluated for each of the hsp27 mutants. These experiments will define functional domains of hsp27 as well as shed light on possible mechanisms of protection. It will be determined whether increased expression of hsp27 can protect human tumor cells in vivo from cytotoxic stresses. The human breast tumor cell lines MCF-7 and MDA-MD-231 will be transfected with an hsp27 expression vector and colonies constitutively expressing hsp27 will be isolated. The hsp27 expressing cell lines will then be injected into nude mice to form tumors. Once tumors are actively growing they will be evaluated for their sensitivity to hyperthermia, radiation, chemotherapy and tamoxifen anti-hormone therapy. These studies will determine whether or not hsp27 can protect human tumor cells in vivo from standard cancer therapies. Finally, to fully understand the regulation of hsp27 the members of hsp27 multigene family will be cloned. Once isolated the different gene products will be characterized for expression and function. The results from the proposed studies will significantly impact our understanding of the regulation and function of hsp27. It will also contribute to our knowledge of how cells respond to toxic stresses, such as those used in certain forms of cancer treatments.
| Hernandez, Inmaculada; Maddison, Lisette A; Wei, Yongli et al. (2003) Prostate-specific expression of p53(R172L) differentially regulates p21, Bax, and mdm2 to inhibit prostate cancer progression and prolong survival. Mol Cancer Res 1:1036-47 |
| Carper, S W; Rocheleau, T A; Cimino, D et al. (1997) Heat shock protein 27 stimulates recovery of RNA and protein synthesis following a heat shock. J Cell Biochem 66:153-64 |
| Lee, Y J; Hou, Z Z; Curetty, L et al. (1994) Regulation of HSP70 and HSP28 gene expression: absence of compensatory interactions. Mol Cell Biochem 137:155-67 |
