This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Uncontrolled cell growth within a tumor results in hypoxia as the metabolic needs of the cells exceed the ability of the tumor vasculature to provide oxygen and nutrients. In response to the hypoxic microenvironment, cells undergo a massive reprogramming of transcription to promote survival. The Hypoxia Inducible Transcription Factors (HIFs) are primary regulators of the hypoxic response and induce expression of several transcripitonal regulators, including several histone demethylases, providing a mechanism for the hypoxic cell to extend or fix the expression of pro-survival genes. One of these histone demethylases, JMJD2B (KDM4B), demethylates tri-methylated histone H3 lysine 9 (H3K9me3) a key marker of repressed chromatin structure. Hypoxic induction of KDM4B may play an important role in activating gene expression to promote tumor growth, and therefore makes an attractive target for the development of new chemotherapeutic agents. In this proposal, the extent to which JMJD2B regulates tumor growth will be tested in the following manner: 1. In vivo using tumor xenograft experiments (Specific Aim 1, Sub-aim 1) 2. In vitro by assaying for cell proliferation, invasion, and angiogenesis as a result of JMJD2B expression (Specific Aim 1, sub-aim 2). 3. Expression microarray experiments will identify new genes regulated by JMJD2B in hypoxia. 4. Chromatin immunoprecipitation will characterize the regulation of key pathways of genes important for the tumorigenic phenotype (Specific Aim 2). The experiments described in this proposal will establish the mechanisms utilized by JMJD2B to regulate tumorigenesis, while identifying new pathways to target for enhanced tumor therapies.
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