Browsing by Subject "Antioncogenes"
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Item Characterization of clone D2: An orphan protein that interacts with peroxisome proliferator-activated receptor gamma(Texas Tech University, 2002-05) Boston, William LeePhosphoenolpymvate carboxykinase (PEPCK) expression is regulated in a tissue specific manner. However, understanding the expression pattern in different tissues is not well documented. We are interested in the adipocyte specific regulation and expression of PEPCK. Our lab had previously identified an adipocyte specific enhancer (ASE) which regulates PEPCK expression through the transcription factor PPARy. To further characterize this effect, the yeast-2-hybrid system was used to characterize what factors bind PPARy in the adipocyte. The screen led to the isolation of a novel protein we have named D2. Our initial hypothesis was that D2 is a cofactor for PPARy. The studies presented here show that D2 is a putative coiled-coil protein whose expression partem does not correlate with that of PPARy. In fact, D2 expression is extremely low in all tissues screened except for several cancer tissues and cell lines. The translated product is highly conserved in various species which suggests an important function. There also seem to be multiple isoforms that potentially arise by the use of an alternative promoter and/or alternative splicing. We also show that D2 expression in both prokaryotic and eukaryotic cells is toxic. The pattern of expression, its conservation among species, and its toxic effects led us to propose that it could be involved in cell cycle control and/or act as a tumor suppressor. Indeed, further investigation revealed that the D2 gene is located in a region on chromosome 9 that is frequently deleted in multiple cancers. Interestingly, there are multiple genes involved in cell cycle control and tumor suppression near the D2 locus. In fact it has been proposed that this chromosomal region could potentially have more tumor suppressors than those previously described. These studies have led to the new working hypothesis that D2 is involved in cell cycle regulation as a novel tumor suppressorItem Characterization of metastasis regulators in human breast cancer: implications for tumor suppressor PTEN and the Rho family of small GTPases(2005) Baugher, Paige Jennette; Dharmawardane, SuranganiCancer metastasis is a multi-faceted process requiring the disregualtion of numerous signaling pathways, including those associated with cell adhesion and motility. Recent data indicates strongly that growth at a primary tumor site and growth at a metastatic site differ by the expression and/or context-dependent function of the metastasis regulator, and that a wide variety of signaling pathways are affected. PTEN (phosphatase and tensin homologue deleted on chromosome ten) then becomes an attractive candidate for a metastasis suppressor, based on its ability to negatively regulate numerous pathways involved in cell survival, cell proliferation, and cell motility. Conversely, the Rho family of small GTPases have become attractive candidates as contributors to metastasis. Rho GTPases regulate numerous signaling pathways involved in cell survival, cell proliferation and cell motility, but they function to enhance these processes instead of inhibiting them. Data presented here demonstrates the ability of PTEN to negatively regulate motility in human metastatic breast cancer cells without causing the cells to undergo apoptosis. PTEN is localized in stimulated cells away from the leading edge, which displaces it from sites of active motility signaling and prevents it from inhibiting these processes. Furthermore, ectopic PTEN expression is shown to downregulate phosphoinositol (3,4,5) triphosphate (PIP3), expression. Therefore, PTEN could be acting as a metastasis suppressor in human breast cancer. Data presented here also demonstrate the ability of the Rac subfamily of Rho GTPases to enhance metastatic properties and contribute to metastasis. Increased Rac activity was shown to correlate with increased metastatic potential in a panel of metastatic human breast cancer cell variants. When activated Rac1 or Rac3 was expressed stably in the least metastatic variant, either isoform was found to enhance adhesion, migration, and invasion in vitro, as well as contribute to pulmonary metastasis in the nude mouse model of experimental metastasis. Conversely, when dominant negative Rac1 or Rac3 was expressed in the most metastatic variant, either isoform was found to decrease adhesion, migration, and invasion in vitro, as well as block pulmonary metastasis in vivo. Therefore, Rac1 and/or Rac3 are found to act as metastasis regulators by negatively regulating metastatic human breast cancer progression.