Alice Y.-C. Liu
Professor

Stress. aging. and molecular chaperones

Our primary research interest is to better understand the biology of aging and age-related decrease in stress resistance. While aging is a complex process with multiple environmental and genetic inputs. there is nevertheless good evidence that oxidation and oxidative damage contribute to the aging process and that genes and cell physiology that confer stress resistance. including resistance to oxidative stress. prolong life-span.

One of the major cellular effect of stress is activation of the heat shock transcription factor 1 (HSF1) and induction of the heat shock transcriptional response. In our research. we showed that induction of the heat shock response (from the activation of HSF1 to the production of HSPs) becomes attenuated in aging human diploid fibroblasts. An attenuated response to stress has also observed in aging animal model systems and in cell culture systems derived from them.To better understand the mechanism of the age-dependent dysfunction of HSF1. we evaluated the role of oxidation-reduction in the regulation of HSF1.Experiments done in vitro provided clear and convincing evidence that that redox is an important mechanism in regulating the structure and function of HSF1. and that oxidation and disulfide crosslinking of cysteines is an off-switch for the activation and trimerization of hHSF1. Our current research effort includes: (1) the use of HSF1 minus cells (immortalized murine embryo fibroblasts derived from hsf1 knockout animals) to test for regulation and function of the wild type and cysteine-site-specific mutants of HSF1 in a cellular context. (ii) analysis of the effects of redox modifiers in the cellular regulation and function of HSF1. and (iii) determining the pathophysiologiclal changes of HSF1 in cell aging and upon oxidative stress. Our long range goal is to better understand the relationship of redox-dependent protein modification. transcription factor regulation. and the molecular basis of transcription factor dysfunction under a variety of physiological and pathophysiological conditions including aging. In so doing. we are hopeful that our work will contribute to the emerging concept of redox as a versatile epigenetic mechanism by which cells regulate important biological processes.

Selected Publications

Khalil S. Luciano J. Chen W. Liu AY. (2006) Dynamic regulation and involvement of the heat shock transcriptional response in arsenic carcinogenesis. J Cell Physiol. 207(2):562-9.

Manalo DJ. Lin Z. Liu AY. (2002) Redox-dependent regulation of the conformation and function of human heat shock factor 1. Biochemistry. 41(8):2580-8.

Park J. Liu AY. (2001) JNK phosphorylates the HSF1 transcriptional activation domain: role of JNK in the regulation of the heat shock response. J Cell Biochem. 82(2):326-38.

Manalo. D. J. and Liu. A. Y.-C. Resolution. detection. and characterization of redox conformers of human HSF1. (2001) J. Biol. Chem. 276: 23554-23561.

Chen. K.Y.. Lu. Jiebo and Liu. A.Y.-C. (2000) The activation of trans-acting factors in response to hypo- and hyper-osmotic stress in mammalian cells. In " Environmental Stressors and Gene Responses." (eds. Storey. K. B.. and Storey. J). Elsevier Science Press. CT.

Lu. J.B.. Park. J.. Liu. A.Y-C. and Chen. K.Y. (2000) Osmotic stress-induced activation of HSF1 DNA binding activity is dramatically attenuated in senescent human cells. J. Cell. Physiol. 184:183-190.

Park. Jeonghyeon and Liu. A. Y.-C. (2000) Pervanadate induces the hyperphosphorylation but not the activaton of human heat shock factor 1. J. Cell. Physiol. 185: 348-357.