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Different ligand responsiveness of human retinoic‐acid‐receptor β‐gene transcription in tumorigenic and non‐tumorigenic cervical‐carcinoma‐derived cell lines is mediated through a large retinoic‐acid‐response domain
Author(s) -
Baust Corinna,
Redpath Leslie,
Schwarz Elisabeth
Publication year - 1996
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19960729)67:3<409::aid-ijc16>3.0.co;2-2
Subject(s) - retinoic acid receptor , retinoic acid , hela , biology , microbiology and biotechnology , reporter gene , retinoic acid receptor beta , cell culture , transfection , cancer research , gene expression , gene , biochemistry , genetics
The retinoic‐acid‐receptor β gene ( RAR ‐β) encodes a suspected tumor suppressor for several types of human carcinomas. RAR ‐β transcription is induced by retinoic acid (RA) through retinoid receptors which bind as heterodimers of a RA‐activated RA receptor (RAR) and a retinoid X receptor to the RA‐responsive element in the RAR ‐β promoter region (βRARE). RA inducibility of RAR ‐β gene expression is often lost or reduced in human carcinoma cells. As previously shown, the RAR ‐β gene is highly RA‐inducible in nontumorigenic HeLa × fibroblast hybrid cells, but neither in HeLa cervical carcinoma cells nor in a tumorigenic hybrid segregant line. We report here that severe reduction of RA‐induced RAR ‐β mRNA levels is a general feature of tumorigenic HeLa × fibroblast segregants. To study the molecular basis of differential RA inducibility, we have performed transient transfection assays in HeLa and nontumorigenic 444 hybrid cells using reporter constructs with different 5′ and internal deletions of the RAR ‐β transcription‐control region. Remarkably, maximal RA inducibility in 444 cells required the integrity of the complete RAR ‐β upstream region. In HeLa cells, all reporter constructs showed only low RA inducibility levels. The differential RA inducibility in 444 and HeLa cells could be conferred by the RAR ‐β upstream region, but not by subfragments of it, on a heterologous RA‐responsive promoter. The data indicate that maximal RA inducibility of RAR ‐β gene transcription in nontumorigenic 444 cells depends on the cooperation of the βRARE with additional upstream elements. All elements together constitute a large RA response domain as the higher‐order transcription control unit. The communication between the upstream elements and the βRARE seems to be disturbed in HeLa cells. Similar defects may be responsible for the loss of RA responsiveness of RAR ‐β gene expression in other human tumors. © 1996 Wiley‐Liss, Inc.