Colon cancers arise as the consequence of the accumulation of mutations and epigenetic alterations in normal cells that lead to the transformation of these cells into cancer. One way through which these genetic and epigenetic alterations affect the behavior of the cells is by deregulating signaling pathways in the cells. The transforming growth factor beta (TGF-beta) signaling pathway is commonly deregulated in colon cancer.
The TGF-beta signaling pathway consists of the secreted ligand, TGF-beta, the heteromeric TGF-beta receptor composed of TGFBR1 and TGFBR2, and the downstream Smad dependent and Smad independent signaling pathways. The TGF-beta signaling pathway regulates proliferation, apoptosis, and differentiation of normal colon epithelium. Mutations in TGFBR2, SMAD4, and SMAD2 have been found commonly in colon cancer and approximately 75% of colon cancers are resistant to TGF-beta.
Thus, we sought to determine whether alterations in the activation of the secreted TGF-beta1 ligand or alterations in the TGFBR2 receptor levels could alter the TGF-beta signaling pathways and potentially be another mechanism through which cancers deregulate TGF-beta signaling. We found that the aberrant methylation of thrombospondin 1 (TSP1), which activates secreted TGF-beta1, is an epigenetic mechanism that attenuates the activation of TGF-beta and the activation of the Smad signaling pathway. The identification of methylated TSP1 in colon cancers is the first demonstration of epigenetic alterations promoting colon cancer formation through repressing TGF-beta signaling.
Our studies of the effect of TGFBR2 expression levels on TGF-beta signaling pathway activation have shown that the activation of Smad independent pathways is dependent on the receptor level. Using a precisely regulated inducible in vitro system, we observed differential activation of the PI3K-AKT and MAPK pathways that varied depending on TGFBR2 expression levels. Furthermore, TGF-beta mediated induction of p21 also varied depending on TGFBR2 expression levels. These results suggest that modulation of TGFBR2 levels can alter the activation of Smad independent signaling pathways and is a potential mechanism for altering the genes that are induced by TGF-beta. Thus, we have determined that the TGF-beta signaling pathway can be altered through suppression of the TGFBR2 and through suppression of mechanisms that affect TGF-beta ligand activation.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03312008-130856 |
| Date | 14 April 2008 |
| Creators | Rojas, Andres |
| Contributors | William Grady, Neil Bhowmick, Mark deCaestecker, Ambra Pozzi, Robert Matusik |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03312008-130856/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0022 seconds