Subcellular localisation of BAG-1 and its regulation of vitamin D receptor-mediated transactivation and involucrin expression in oral keratinocytes: implications for oral carcinogenesis.
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 1alpha,25-dihydroxyvitamin D3. 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 1alpha,25-dihydroxyvitamin D3. By contrast to the cytoplasmic BAG-1 isoforms, BAG-1L may act to suppress tumorigenesis.
Lee
San San
SS
Department of Oral and Dental Science, University of Bristol, Lower Maudlin Street, Bristol BS1 2LY, UK.
Crabb
Simon J
SJ
Janghra
Nari
N
Carlberg
Carsten
C
Williams
Ann C
AC
Cutress
Ramsey I
RI
Packham
Graham
G
Hague
Angela
A
D000595:Amino Acid Sequence; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D015675:Osteocalcin / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology
C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D011498:Protein Precursors; D018167:Receptors, Calcitriol; D014157:Transcription Factors; C118756:dihydroxy-vitamin D3; D015675:Osteocalcin; D014807:Vitamin D; C032253:involucrin