A joint project of the Graduate School, Peabody College, and the Jean & Alexander Heard Library

Title page for ETD etd-03312004-161742

Type of Document Dissertation
Author Gupta, Rajnish Anand
Author's Email Address rajnish.gupta@vanderbilt.edu
URN etd-03312004-161742
Title Peroxisome Proliferator-Activated Receptor gamma (PPARg) is a Regulator of Colorectal Cancer Cell Growth and Differentiation
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Raymond DuBois, MD, PhD Committee Chair
Al Reynolds Committee Member
Daryl Granner Committee Member
Mark Magnuson Committee Member
Stephen Brandt Committee Member
  • prostaglandins
  • nuclear hormone receptor
  • colon cancer
Date of Defense 2001-07-30
Availability unrestricted
Peroxisome prolferator-activated receptor g (PPARg) is a member of the nuclear hormone receptor superfamily and is ligand activated by polyunsaturated fatty acids, certain arachadonic acid metabolites, and class of synthetic compounds with insulin sensitizing activity known as thiazoidinediones. PPARg is strongly expressed in the post-mitotic epithelial compartment of the normal human large intestine. Exposure of a panel of human colorectal cancer cell lines to PPARg agonists leads to a decrease in cell growth that is associated with a partial G1 arrest and increased levels of the cyclin dependent kinase inhibitor p21. A subset of these cells lines were resistant to the growth inhibitory effects of PPARg ligands. All four of the resistant lines contained a point mutation at codon 422 of the ligand binding domain of PPARg. Further studies suggested this mutation leads to a loss of functional PPARg due to a defect in the ability of the receptor to repress the transcrption of some target genes in the absence of exogneous ligand. Microrray technology was used to understand the genomic response of intestinal epithelial cells exposed to PPARg agonists. PPARg selective target genes included proteins linked to regulation of cell growth, colon epithelial cell maturation, and immune modulation. One of these genes, Transforming Growth Factor b Clone-22 (TSC-22), is a leucine zipper containing transcription factor that is capable of repressing gene transcription. Inhibition of TSC-22 using a dominant-negative construct partially blocked the ability of PPARg to induce growth arrest. In summary, these studies collective demonstrate that PPARg is a regulator of colorectal cancer cell growth and differentiation.
  Filename       Size       Approximate Download Time (Hours:Minutes:Seconds) 
 28.8 Modem   56K Modem   ISDN (64 Kb)   ISDN (128 Kb)   Higher-speed Access 
  01.thesis.pdf 71.09 Kb 00:00:19 00:00:10 00:00:08 00:00:04 < 00:00:01
  02.thesis.pdf 13.91 Mb 01:04:23 00:33:06 00:28:58 00:14:29 00:01:14

Browse All Available ETDs by ( Author | Department )

If you have more questions or technical problems, please Contact LITS.