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    • Albert Einstein College of Medicine: Doctoral Dissertations
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    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
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    Insights into caveolae, the caveolins, and the signaling hypothesis: A biochemical, cellular, and genetic approach

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    Date
    2003
    Author
    Razani, Babak
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    Abstract
    A major advance in the study of caveolae membrane domains was the discovery of the 21--24 kDa "caveolar protein marker", named caveolin-1 (Cav-1).;In the initial stages of this thesis, I focused on the role of Cav-1 in signal transduction and tumorigenesis, which is a primary thrust of our laboratory. Specifically, I studied the ability of Cav-1 to negatively regulate the signaling capacity of two signaling cascades---the cAMP/PKA pathway and the TGFbeta/SMAD pathway. Through a series of in vivo and in vitro experiments, I was able to show that several components of these signaling pathways reside in caveolae and that caveolin-1 is able to inhibit their functional activity. Further molecular dissection indicated that the primary mechanism of this inhibition occurred by the direct binding of the Cav-1 scaffolding domain to the central kinase in each pathway, i.e. the PKA catalytic subunit and the TGFbeta Type I receptor. In relation to tumorigenesis. I showed that caveolin-1 expression is dramatically down-regulated in several different epithelial-derived cancer cell lines, indicating that Cav-1 is possibly an important target during transformation. Interestingly, an analysis of this downregulation led me to identify p53 as a previously unrecognized mediator of Cav-1 transcriptional responses.;I focused the latter efforts of my thesis work on the generation and characterization of mice deficient in the caveolin-1 and -2 genes. Initial characterization of the Cav-1 null mice indicated a complete absence of morphologically identifiable caveolae, thereby proving that Cav-1 is required to drive caveolar biogenesis. Furthermore, these mice showed endocytic abnormalities, hyper-proliferation of certain cell types, pulmonary defects, and compromised vascular tone due to eNOS hyper-activation. Interestingly, follow-up of these mice into old-age revealed another very interesting phenotype, i.e., an inability of Cav-1 null mice to gain weight, an observation which I subsequently analyzed in detail. I showed that Cav-1 null mice are resistant to diet-induced obesity due to severe adipocyte abnormalities; a condition that results in severe derangements in triglyceride/free fatty acids metabolism.;A confounding variable in the characterization of Cav-1 null mice was the fact that the Cav-2 protein was also drastically reduced in expression (due to destabilization). As a result, neither gene could be directly implicated in the observed phenotypes. My independent work on the generation of caveolin-2 null mice was extremely useful in this respect. As Cav-2 null mice show little to no effect on Cav-1 expression, any phenotypic overlaps in these mice would reflect a selective importance for Cav-2. Interestingly, with the exception of identical pulmonary abnormalities, none of the other major pathologies observed in Cav-1 deficient mice were recapitulated in the Cav-2 null setting. (Abstract shortened by UMI.).
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    https://yulib002.mc.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3106720
    https://hdl.handle.net/20.500.12202/656
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    • Albert Einstein College of Medicine: Doctoral Dissertations [1674]

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