Tissue-specific defects in caveolin-deficient mice
Park, David S.
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The ability of caveolin-l to inhibit the activity of various kinases raised the possibility that it may act as a tumor suppressor. We investigated this hypothesis by examining whether caveolin-1 expression could be down-regulated by Myc-family oncogenes. Using a tamoxifen-activatible c-Myc-ER system in NIH-3T3, we reported that caveolin-1 expression was down-regulated by Myc-isoforms by directly binding the initiator (INR) element in the caveolin-1 promoter. Moreover, we showed that modulation of caveolin-1 protein levels, via an adenoviral vector approach, inversely correlated with Myc-induced cell transformation. Our results indicate that caveolin-1 is a direct target of Myc repression, and they also provide evidence for an additional mechanism by which Myc repression can elicit a malignant phenotype.;We reported that caveolin-1 expression, which is abundantly expressed in quiescent mammary epithelium, is significantly down-regulated during late pregnancy and lactation. We found that caveolin-1 repression was due to activation of the prolactin receptor-signaling cascade. To examine the functional consequences of caveolin-1 down-regulation, we constitutively expressed caveolin-1 in HC11 cells, which can differentiate and produce milk proteins in culture. Heterologous caveolin-1 expression during prolactin treatment abrogated milk protein synthesis by inhibiting the Jak2/STAT5a signaling pathway. Accordingly, Cav-1 deficient mice exhibited precocious mammary development during pregnancy and lactation. Biochemical analysis revealed accelerated milk protein synthesis and hyperactivation of STAT5a and MAPK pathways.;We generated caveolin-1 and -3 double knockout mice (Cav-1/3 dKO), which distinctly lack morphologically identifiable caveolae in all tissue examined. Because caveolin-1 knockout mice also lack caveolin-2 expression, Cav-1/3 dKO mice are also caveolin-deficient mice. Although the mice were viable, they exhibited a hypertrophy/dilated cardiomyopathic phenotype. The heart defect was analyzed using MRI and echocardiographic studies, which revealed marked hypertrophy and dilation resulting in a 40% reduction in fractional shortening (a measure of cardiac function). Histological examination of the cardiac tissue demonstrated profound cardiac myocyte disorganization, hypertrophy and myocytolysis. Cav-1/3 dKO hearts also exhibited a reversion to fetal programming as shown by the upregulation of atrial natriuertic factor (ANF) in ventricular tissue. Taken together, these results support a role for caveolae vesicles in the development and/or maintenance of normal cardiac architecture and function. (Abstract shortened by UMI.).