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Increased P-glycoprotein messenger RNA stability in rat liver tumors in vivo

✍ Scribed by Chow Hwee Lee; Grace Bradley; Victor Ling

Publisher
John Wiley and Sons
Year
1998
Tongue
English
Weight
333 KB
Volume
177
Category
Article
ISSN
0021-9541

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✦ Synopsis

P-glycoproteins (Pgp) are comprised of a small family of plasma membrane proteins whose abundance in cultured cells is often associated with the multidrug resistance phenotype. Overexpression of Pgp has been observed in many types of human cancers, but the molecular basis for this overexpression has not been established. We have used primary monolayer cultures of adult rat hepatocytes and a stepwise model of rat liver carcinogenesis to study the regulation of Pgp gene expression. We observed a marked overexpression of Pgp, specifically the class II Pgp, in both systems. In addition, we observed that a number of unrelated genes including a-tubulin, b-actin, g-actin, cytokeratin 8, cytokeratin 18, and cmyc are overexpressed in cultured hepatocytes, and they are also overexpressed during liver carcinogenesis and in transplantable tumors. Nuclear run-on assays showed no increase in the transcriptional activity of Pgp genes in transplantable liver tumors compared to normal liver. Studies of in vivo mRNA stability, however, revealed that all three Pgp mRNAs were relatively stable in transplantable liver tumors (t 1/2 ú 12 h), in contrast to what was found in normal liver (t 1/2 õ 2 h). In addition, mRNA for several other genes, including a-tubulin, c-myc, and cyclin D1, all appear to be stabilized in the tumors. These findings suggest that the overexpression of Pgp genes in rat liver tumors may be the result of a mechanism involving stabilization of a diverse group of mRNAs.

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