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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), pp. 3222-3238. (doi:10.1016/j.yexcr.2007.06.010).

Record type: Article

Abstract

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.

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More information

Published date: 10 September 2007
Keywords: promoter, protein, dna-binding, transcriptional activity, 24-hydroxylase, 1, cancer, transcription, nucleolar localisation sequence, in-vitro, oral keratinocytes, 25-dihydroxyvitamin d-3

Identifiers

Local EPrints ID: 62827
URI: http://eprints.soton.ac.uk/id/eprint/62827
ISSN: 0014-4827
PURE UUID: b6479470-9c22-4b58-8380-e8884e56cc7a

Catalogue record

Date deposited: 11 Sep 2008
Last modified: 17 Jul 2017 14:19

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