Publikationsserver der RWTH Aachen University
Expressionsstudien und Mutationsanalyse des TGF-[beta]-Antagonisten Smad7 in menschlichen hepatozellulären Karzinomen
Abstract
dc:descriptionMembers of the transforming growth factor Beta (TGF-Beta) family transmit signals from membrane to nucleus via intracellular proteins known as Smads. After binding of TGF-Beta to the receptor complex (consisting of TGF-Beta receptor I and II), Smad2 and/or Smad3 are activated by phosphorylation through TGF-Beta receptor I (TGF-BetaRI). Phosphorylated Smad 2/3 subsequently heterodimerize with Smad4 and form a transcriptionally active complex. Smad7 has been identified, a player that antagonizes rather than transduces TGF-Beta-family signals by acting downstream of TGF-Beta receptors. TGF-Beta rapidly induces the expression of Smad7 mRNA, suggesting participation in a negative feedback loop to control TGF-Beta-responses. Most cancer cells show resistance to TGF-Beta induced growth inhibition, suggesting that loss of TGF-Beta responsiveness is an important step in the carcinogenesis process. Mutations in the TGF-Beta type II receptor (TGF-BetaRII), Smad2 and Smad4 genes have been observed in several human cancers that are insensitive against the anti-proliferative signals of TGF-Beta. Most of the TGF-BetaRII and Smad4 mutations have been confirmed to completely inactivate the TGF-Beta signal pathway. Thus, TGF-BetaRII and Smad4 are considered to be tumor suppressor genes, and their mutational inactivation plays an important role in human carcinogenesis. In hepatocellular carcinoma (HCC), perturbations at the TGF-Beta-receptor smad level do not appear to be as frequent as they are in, e.g., colon or pancreatic cancer. Yet a great deal of hepatocellular carcinoma show resistance to TGF-Beta growth inhibition. The identification of the antagonistic Smad7 raises the possibility that constitutive overexpression may cause interruption of TGF-Beta signal transduction. Therefore, the expression of Smad7 in 20 HCC samples and corresponding healthy liver tissues from the same patients was investigated. Increased expression of Smad7 was found in 16 of 20 HCC samples compared to healthy liver of the same patients. In addition to this mutations in an almost completely conserved region of the Smad7 promoter were investigated. Mutations were not found. The results suggest that Smad7 overexpression is a possible strategy to escape TGF-Beta induced growth inhibition.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2005
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Bauche, Britta Ellen
- Contributors dc:contributor
-
- Dooley, Steven
Subjects
dc:subject × 5Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- ger