The Role of GADD34 (Growth Arrest and DNA Damage-Inducible Protein) in Regulating Apoptosis, Proliferation, and Protein Synthesis in Human Breast Cancer Cells
Abstract
GADD34 is a stress-induced proteins implicated in the control of protein synthesis and apoptosis. It is a major target of the oncogene c-myc. Myc is widely implicated in breast cancer and potently inhibits GADD34 expression. The goal of this proposal is to better understand the mechanism of GADD34 induced apoptosis and the implications of this to human breast cancer. Toward this goal we have analyzed the regulation of eIF2 alpha dephosphorylation by GADD34 and by its binding partner Inhibitor-I. We have demonstrated that proper subcellular localization of GADD34 is necessary for function. We have identified a novel domain that targets GADD34 to the endoplasmic reticulum, and a domain involved in PP1 binding. We also examined the role of 1-1, a GADD34 interacting protein that inhibits PP1, in inhibiting eIF2 alpha dephosphorylation and identified a novel domain necessary for the in vivo function of 1-1. We also demonstrated that this domain is absent in 2 alternate splice forms of 1-1, 1-1 alpha and 1-1 beta, which are weaker inhibitors of eIF2 alpha dephosphorylation. We have also demonstrated that GADD34 protein levels are elevated in human cancer cells in response to a variety of stressed. Interestingly, p38 MAP kinase is required for GADD34 induction by aresnite, but not endoplasmic-reticulum stress. GADD34 is also a rapidly degraded protein, consistent with a temporal regulation of stress-signaling. This work has lead to a better understanding of GADD34 function in cancer cell, and may lead to better anti-breast-cancer drugs targeting this apoptotic pathway.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2004
- Accession Number
- ADA427916
Entities
People
- Douglas C. Weiser
Organizations
- Duke University Hospital