Aberrant DNA methylation of cyclin D2 and p27 genes in rodent pituitary tumor cell lines correlates with specific gene expression |
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Authors: | Xiang Qian MD PhD Long Jin MD Dr Ricardo V Lloyd MD PhD |
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Institution: | (1) Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, 200 First Street, SW, 55905 Rochester, MN |
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Abstract: | We previously reported that increased DNA methylation was an important mechanism of silencing the p27 gene in some pituitary
tumor cell lines 1]. DNA methylation correlated inversely with p27 gene expression. The p27 and cyclin D2 genes are located
in the same region of mouse chromosome 6, rat chromosome 4, and human chromosome 12p13. Because both genes are located in
the same gene cluster, we investigated whether methylation was a principal mechanism regulating cyclin D2 as well as p27 expression
in rodent pituitary cell lines. Bisulfite genomic sequencing showed that the normally unmethylated cytosines of the p27 gene
in normal pituitary (NP) were extensively methylated in GH3 and GHRH-CL1 cells, but not in AtT 20, αT3-1 and LβT2 cells; but cyclin D2 was extensively inactivated in various pituitary tumor cell lines by increased DNA methylation. These abnormalities of methylation in p27 and cyclin
D2 genes occurred with different frequencies in five pituitary tumor cell lines with 100% (5/5) methylation of the cyclin
D2 gene and 40% (2/5) methylation of the p27 gene. Treatment with the methyl transferase inhibitor 5′-aza-2′-deoxycytidine
(AZAdC) increased expression of cyclin D2 and p27 in GH3 and GHRH-CL1 pituitary tumor cells. There was a correlation between
hypermethylation and gene expression. GH3 tumors implanted into Wistar-Furth rats in vivo did not change the methylation status of the p27 and cyclin D2 genes. These
data indicate a coordinately reduced expression of these two linked genes in most rodent pituitary tumor cell lines and suggest
that methylation of cyclin D2 and p27 might occur in a “hot spot” in this gene-rich cluster.
Supported in part by NIH CA 37231 and CA 42951 |
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Keywords: | Pituitary tumor cell cycle gene DNA methylation bisulfite |
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