Mechanisms of RASSF1A tumor suppressor gene inactivation by de novo methylation of the promoter CpG island during carcinogenesis
Final Report Abstract
The Ras Association Domain Family 1 (RASSF1) tumor suppressor gene has been located in 3p21.3 a region, which is frequently lost in a variety of human tumors. The RASSF1 gene consists of two major transcripts, termed RASSF1A and RASSF1C, which are expressed from two distinct CpG island promoters. Both transcripts are present in normal human tissues. In contrast to RASSF1C, the RASSF1A message is missing in a variety of human cancer cell lines and primary tumors. Silencing of RASSF1A transcript has been correlated to aberrant DNA methylation ofthe RASSF1A CpG island. Methylation profiling of breast tumors suggest that DNA methylation spreads from the first exon into the CpG 22 islands area. We have examined the functional relationship between DNA methylation, histone modification and RASSF1A expression in proliferating human epithelial cells and revealed that the epigenetical inactivation of the RASSF1A promoter is associated with de novo methylation of the promoter and repression of chromatin state. However, it is still unknown which mechanism initiates the epigenetical inactivation of tumor suppressor genes during neoplastic transformation.
Publications
- Epigenetic inactivation of the Ras-association domain family 1 (RASSF1A) gene and its function in human carcinogenesis. Histol Histopathol. 2003 Apr;18(2):665-77
Dammann R, Schagdarsurengin U, Strunnikova M, Rastetter M, Seidel C, Liu L, Tommasi S, Pfeifer GP
- Isolation, Charakterisierung und Funktion des Ras Assoziationsdomänen Familie 1 Gens aus dem Tumorsuppressionslocus 3p21.3 mit besonderer Berücksichtigung seiner epigenetischen Inaktivierung in humanen Tumoren. Habilitationschrift, Universität Halle-Wittenberg, 2004
Dammann R
- Characterization of the epigenetical inactivation of the tumor suppressor gene RASSFI A in human mammary epithelial cells. Diss., Universität Halle-Wittenberg, 2005
Hahn M
- Chromatin inactivation precedes de novo DNA methylation during the progressive epigenetic silencing of the RASSF1A promoter. Mol Cell Biol. 2005 May;25(10):3923-33
Strunnikova M, Schagdarsurengin U, Kehlen A, Garbe JC, Stampfer MR, Dammann R
- CpG island methylation and expression of tumour-associated genes in lung carcinoma. Eur J Cancer. 2005 May;41 (8); 1223-36
Dammann R, Strunnikova M, Schagdarsurengin U, Rastetter M, Papritz M, Hattenhorst UE, Hofmann HS, Silber RE, Burdach S, Hansen G
- The tumor suppressor RASSF1A in human carcinogenesis: an update. Histol Histopathol. 2005 Apr;20(2):645-63
Dammann R, Schagdarsurengin U, Seidel C, Strunnikova M, Rastetter M, Baier K, Pfeifer GP
