Both basic and clinical studies demonstrate that low oxygen conditions in solid tumors (hypoxia/anoxia) are an important determinant of malignant progression. It is becoming clear that a network of transcription factors mediates the ability of normal and transformed cells to adapt to changes in tumor oxygenation. The studies described in this application are focused on understanding the role and biological importance of the master transcription factor c-Jun/AP-1 in this network. Our earlier research demonstrated that exposure of transformed cells to hypoxia/anoxia induces expression of the c-jun proto-oncogene and activates protein kinase and phosphatase activity that regulate the phosphorylation state of c-Jun/AP-1. Here we present the fundamental finding that the induction of c-jun expression and c-Jun phosphorylation by hypoxia has two components: a late component that is completely dependent on the transcription factor HIF-1, and an early component that is independent of HIF-1. HIF-1 is a ubiquitous mediator of hypoxia- responsive gene expression in mammalian cells. Based on this critical finding, we hypothesize that c-Jun/AP-1 and HIF-1 cooperate to regulate gene expression in hypoxic or anoxic tumor microenvironments. Moreover, because of the resemblance of the early component of hypoxia-inducible c-jun expression to the classic induction of immediate-early genes by serum growth factors, we hypothesize that the response of c-jun and c-Jun/AP-1 to physiological hypoxia overlaps with the general immediate- early response. To investigate these hypotheses, we propose two Specific Aims.
In Aim 1, we will identify hypoxia-responsive phosphorylation sites in c-Jun and determine the role of c-Jun phosphorylation in promoting the growth of tumor xenografts. These studies will determine the relationship between hypoxia- responsive c-Jun phosphorylation and proliferation in the tumor microenvironment.
In Aim 2, we will investigate specific serum- responsive pathways responsible for the immediate-early induction of c-jun expression by hypoxia. These studies will relate the serum-dependent immediate-early response to cellular oxygen sensing mechanisms. They will also identify new mammalian transcriptional regulators responsive to a wide range of low oxygen conditions.
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