Role of the ras-MAPK signaling pathway in the DNA methyltransferase response to DNA hypomethylation.
Our group reported that inhibiting DNA methylation in human T cells increases DNA methyltransferase expression and activity, and suggested that this may represent a response to DNA hypomethylation. The increase correlates with increases in Ha-ras and c-jun, suggesting that increased signaling through the ras-MAPK pathway, due to overexpression of some elements, may be responsible. However, whether human DNA MTase is regulated by the ras-MAPK pathway, and whether overexpression of elements in this pathway will increase DNA MTase, is unknown. We report that treating cells with a DNA methylation inhibitor increases transcription regulated by a putative DNA MTase promoter, and that this increase requires AP-1 sites. Additional studies demonstrate that overexpression of an unmutated Ha-ras causes an increase in DNA MTase, and that human T cell DNA MTase can be decreased by inhibiting signaling through the ras-MAPK pathway. Together, these studies suggest that human T cell DNA MTase is regulated through the ras-MAPK pathway, and that overexpression of Ha-ras is sufficient to increase DNA MTase expression. These results thus provide a mechanism for the increase in DNA MTase observed after inducing DNA hypomethylation, a response which may have relevance to some disease states.
Deng
C
C
Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0940, USA.
Yang
J
J
Scott
J
J
Hanash
S
S
Richardson
B C
BC
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D019175:DNA Methylation; D017931:DNA Primers; D015257:DNA-Cytosine Methylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction
D017931:DNA Primers; D015257:DNA-Cytosine Methylases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D015689:Oncogene Protein p21(ras)