Subcellular localisation of BAG-1 and its regulation of vitamin D receptor-mediated transactivation and involucrin expression in oral keratinocytes: Implications for oral carcinogenesis

Journal Article · Mon Sep 10 04:00:00 EDT 2007 · Experimental Cell Research

DOI:https://doi.org/10.1016/j.yexcr.2007.06.010· OSTI ID:21045888

Lee, San San ^[1]; Crabb, Simon J ^[2]; Janghra, Nari ^[1]; Carlberg, Carsten ^[3]; Williams, Ann C ^[4]; Cutress, Ramsey I; Packham, Graham ^[2]; Hague, Angela ^[1]

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1. Department of Oral and Dental Science, University of Bristol, Lower Maudlin Street, Bristol BS1 2LY (United Kingdom)
2. Cancer Research UK Clinical Centre, University of Southampton School of Medicine, Tremona Road, Southampton, SO16 6YD (United Kingdom)
3. Department of Biochemistry, University of Kuopio, PO Box 1627, 70211 Kuopio (Finland)
4. Cancer Research UK Colorectal Tumour Biology Research Group, Department of Cellular and Molecular Pathology, School of Medical Sciences, University Walk, Bristol BS8 1TD (United Kingdom)

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-1S, enhanced VDR transactivation in response to 1{alpha},25-dihydroxyvitamin D{sub 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{sub 3}. By contrast to the cytoplasmic BAG-1 isoforms, BAG-1L may act to suppress tumorigenesis.

• OSTI ID: 21045888
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 15 Vol. 313; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANDROGENS
ANIMAL CELLS
ANTIGENS
CARCINOGENESIS
CATTLE
GENE REGULATION
GLUCOCORTICOIDS
GROWTH FACTORS
HYDROXYLASES
NEOPLASMS
PHOSPHATES
RECEPTORS
RETINOIC ACID
VITAMIN D