An ACTH-producing small cell lung cancer expresses an aberrant glucocorticoid receptor (GR) transcript from a normal GR gene

L. L. Parks, M. K. Tumey, W. J. Kovacs

Research output: Contribution to journalArticle

Abstract

ACTH secretion from non-pituitary tumors such as small cell lung carcinomas is generally not suppressible by exogenous glucocorticoids. We postulated that defects in the GR signaling system might be responsible for this apparent glucocorticoid resistance. In a cell line (DMS-79) derived from one such ectopic ACTH-producing tumor we have found evidence for expression of a truncated, nonfunctional form of GR in which the sequences encoded by exons 8 and 9 are replaced by sequence unmatched in the DNA databases. We sought to identify the origin of the novel GR mRNA sequence and to determine whether the truncated DMS-79 GR results from a structural alteration of the GR gene (e.g., deletion of exons 8 and 9). When DMS-79 cell DNA was examined by Southern blot analysis no major structural alteration of the GR gene was discernible. Southern blotting of cosmid clones of the normal GR gene (the gift of Dr. S. Detera-Wadleigh, NIH) revealed that the novel sequence in DMS-79 cell GR mRNA is derived from intron G, between exons 7 and 8. No splice donor or acceptor site mutations were found in PCR-amplified DMS-79 DNA from the exon 7-intron G or intron G-exon 8 boundaries. Further sequencing indicated that the aberrant GR transcript appears to use a consensus polyadenylation site found 3653 base pairs into the normal intron G. The protein encoded by this mRNA would lack the steroid-binding domain. We conclude that abnormal GR pre-mRNA processing rather than a GR gene mutation may confer the phenotype of glucocorticoid resistance on these tumor cells.

Original languageEnglish (US)
Pages (from-to)30A
JournalJournal of Investigative Medicine
Volume44
Issue number1
StatePublished - Jan 1 1996

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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