Show simple item record

dc.contributor.authorEngelman, Jeffrey Adam
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 61-09, Section: B, page: 4563.;Advisors: Michael P. Lisanti.
dc.description.abstractCaveolae are small (∼50--100nm) invaginations of the plasma membrane. Signal transduction molecules are highly enriched in these domains. Caveolae are most highly expressed in terminally-differentiated cell types such as adipocytes, endothelial cells, muscle cells, and epithelial cells. Caveolins are a family of proteins that constitute the principal components of caveolae. Recent experiments have demonstrated that caveohn-1 functionally interacts with many signaling molecules.;Caveolae are abundant in NIH 3T3 fibroblasts, but are absent in fibroblasts transformed by a wide variety of activated oncogenes such as H-Ras (G12V) and v-Abl. In these cells, caveolin-1 mRNA and protein expression are lost or reduced. However, it was unknown whether the down-regulation of caveolin-1 protein and caveolar structures contributes to their transformed phenotype.;The data in this thesis support the hypothesis that caveolin-1 protein is downregulated in response to oncogenic cellular transformation and that this downregulation contributes to the transformed phenotype. Caveolin-1 was expressed in H-Ras (G12V) and v-Abl transformed cells under the control of an inducible expression system. Expression of caveolin-1 abrogated the ability of these cells to grow in soft agar. Furthermore, induction of caveolin-1 led to the appearance of caveolae as determined by electron microscopy. We have examined the expression of caveolin-1 in a multitude of excised tumors from a variety of mouse models of mammary carcinoma. In all cancer types examined, caveohn-1 protein was absent.;We discovered that p42/44 MAP kinase activation inhibits caveolin-1 expression. In contrast, caveolin-1 is dramatically upregulated during the course of differentiation of 3T3-L1 fibroblasts to adipocytes. Treatment of 3T3-L1 fibroblasts with inhibitors of the p42/44 MAP Kinase and the p38 MAP Kinase in fibroblasts did not affect caveolin-1 expression. However, we discovered that inhibitors of p38, but not p42/44, MAP kinase completely block 3T3-L1 adipocyte differentiation. Furthermore, we constructed a 3T3-L1 cell line harboring an inducible dominant-negative p38. Expression of the dominant-negative p38 inhibited adipogenesis. We show that adipogenic transcription factors, such as C/EBPbeta, are direct p38 targets and thereby provide at least one mechanism by which p38 promotes adipogenesis.;In addition, we constructed 3T3-L1 cell lines harboring an inducible, constitutively active MKK6 (a specific activator of p38). Activation of p38 was sufficient to trigger 3T3-L1 differentiation in the absence of normally required hormonal stimulation. However, activation of p38 in the adipocytes led to apoptosis. (Abstract shortened by UMI.).
dc.publisherProQuest Dissertations & Theses
dc.subjectMolecular biology.
dc.titleThe roles of caveolin-1 and MAP kinase pathways in cellular transformation and differentiation

Files in this item


There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record