The long-term objective of this research plan is to understand the molecular mechanisms that allow eukaryotic cells to recognize and respond to various physiological stresses such as nutrient deprivation or perturbation of intracellular calcium. Such conditions can be experienced by neoplastic cells. Eukaryotic cells respond to cellular stress by inducing growth arrest and up-regulating the synthesis of a set of molecular chaperones, including BiP/GRP78, that are present in the endoplasmic reticulum (ER) and protect the cell from the deleterious accumulation of misfolded proteins. Preliminary evidence indicates that a stress-induced transcription factor, gadd153/CHOP, a protein that can induce growth arrest and modulate the expression of certain genes, is induced via the same pathway as the stress-regulated ER chaperones. The hypothesis that a relationship exists between the induction of CHOP and the increased synthesis of the ER chaperones that occur in response to cellular stress will be tested. The studies will further our understanding of the biology of both the CHOP transcription factor and the ER chaperones and provide important information concerning how cells manage growth and survival in times of physiological stress.
| Lee, Y K; Brewer, J W; Hellman, R et al. (1999) BiP and immunoglobulin light chain cooperate to control the folding of heavy chain and ensure the fidelity of immunoglobulin assembly. Mol Biol Cell 10:2209-19 |
| Lawson, B; Brewer, J W; Hendershot, L M (1998) Geldanamycin, an hsp90/GRP94-binding drug, induces increased transcription of endoplasmic reticulum (ER) chaperones via the ER stress pathway. J Cell Physiol 174:170-8 |
| Brewer, J W; Cleveland, J L; Hendershot, L M (1997) A pathway distinct from the mammalian unfolded protein response regulates expression of endoplasmic reticulum chaperones in non-stressed cells. EMBO J 16:7207-16 |
