Subcellular localisation of BAG-1 and its regulation of vitamin D receptor-mediated transactivation and involucrin expression in oral keratinocytes: Implications for oral carcinogenesis
Lee, San San, Crabb, Simon J., Janghra, Nari, Carlber, Carsten, Williams, Ann C., Cutress, Ramsey I., Packham, Graham and Hague, Graham (2007) Subcellular localisation of BAG-1 and its regulation of vitamin D receptor-mediated transactivation and involucrin expression in oral keratinocytes: Implications for oral carcinogenesis. Experimental Cell Research, 313, (15), 3222-3238. (doi:10.1016/j.yexcr.2007.06.010).
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In oral cancers, cytoplasmic BAG-1 overexpression is a marker of poor prognosis. BAG-1 regulates cellular growth, differentiation and survival through interactions with diverse proteins, including the vitamin D receptor (VDR), a key regulator of keratinocyte growth and differentiation. BAG-1 is expressed ubiquitously in human cells as three major isoforms of 50 kDa (BAG-1L), 46 kDa (BAG-1M) and 36 kDa (BAG-1S) from a single mRNA. In oral keratinocytes BAG-1L, but not BAG-1M and BAG-IS, enhanced VDR transactivation in response to 1 alpha,2S-dihydroxyvitamin D-3. BAG-1L was nucleoplasmic and nucleolar, whereas BAG-1S and BAG-1M were cytoplasmic and nucleoplasmic in localisation. Having identified the nucleolar localisation sequence in BAG-1L, we showed that mutation of this sequence did not prevent BAG-1L from potentiating VDR activity. BAG-1L also potentiated transactivation of known vitamin-D-responsive gene promoters, osteocalcin and 24-hydroxylase, and enhanced VDR-dependent transcription and protein expression of the keratinocyte differentiation marker, involucrin. These results demonstrate endogenous gene regulation by BAG-1L by potentiating nuclear hormone receptor function and suggest a role for BAG-1L in 24-hydroxylase regulation of vitamin D metabolism and the cellular response of oral keratinocytes to 1 alpha,25-dihydroxyvitamin D-3. By contrast to the cytoplasmic BAG-1 isoforms, BAG-1L may act to suppress tumorigenesis.
|Digital Object Identifier (DOI):||doi:10.1016/j.yexcr.2007.06.010|
|Keywords:||promoter, protein, dna-binding, transcriptional activity, 24-hydroxylase,1, cancer, transcription, nucleolar localisation sequence, in-vitro, oral keratinocytes,25-dihydroxyvitamin d-3|
|Subjects:||R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RD Surgery
|Divisions :||University Structure - Pre August 2011 > School of Medicine
University Structure - Pre August 2011 > School of Medicine > Cancer Sciences
University Structure - Pre August 2011 > School of Medicine > Developmental Origins of Health and Disease
|Accepted Date and Publication Date:||
|Date Deposited:||11 Sep 2008|
|Last Modified:||31 Mar 2016 12:46|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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