STRESS RESPONSES IN MAMMALIAN CELLS

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DESCRIPTION: Angiogenesis is vital for tumor growth and is widely believed to be a factor in tumor metastasis. Recent work by Folkman and his colleagues has demonstrated that inhibition of angiogenesis can keep dormant micro-metastases from growing. Most work on angiogenesis in tumors has focused on how to preven tumor growth and metastasis and not at what mechanisms, both cellular and environmental, are involved in the process. Stress caused by alteration of the micro- or macroenvironment of a cell (e.g. radiation, high temperature, hypoxia, and starvation) has been known to trigger the highly complex cellular stress management system for many years. Recent evidence from our laboratories has also shown that, in addition to the well-known stress proteins, environmental stress can induce the synthesis of growth factor such as basic fibroblast growth factor (bFGF). The observation of the induction of these angiogenic proteins under these circumstances could have significant implications on the process of tumorigenesis. Once the tumor initiation has occurred, the solid tumor cells must promote the formation of new blood vessel to provide nutrients and oxygen; otherwise, they can not grow beyond a very small size. Thus, preventing the formation of new vessels has been a promising new approach to treat cancer patients. In order to inhibit the growth of new vessels, we need to understand the mechanisms of tumor vascularization. It is known that the growth of new vessels is stimulated by angiogenic factors. We proposed that angiogenic factors, i.e., bFGF can be induced by environmental stresses such as heat shock, radiation, hypoglycemia, and hypoxia. Environmental stresses activate special transcription factors, which are referred to as activating protein-1 (AP-1). The AP-1 factors are composed of dimeric complexes formed between three Jun family members (C-Jun, Jun B, Jun D and four Fos family members (c-Fos, Fos B, Fra-1, and Fra-2). The activated AP-1 factors bind the regulatory region of BFGF gene, which then triggers the gene expression. Moreover, AP-1 factors cooperate with other regulatory factor such as Ets-1 protein for the regulation of bFGF gene expression. We believe that investigating the involvement of AP-1 factors in bFGF gene regulation wil provide insight into understanding the mechanism of stress-induced tumor growt and metastasis at the molecular level as well as enable us to improve the efficacy of clinical therapy.