Research article
Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing
-
* Corresponding author: Scott M Kahn smk1@columbia.edu
1 Department of Urology, Columbia University, New York, NY, 10032, USA
2 Institute for Health Sciences, St Luke's-Roosevelt Hospital, 432 W 58th St Room 405, New York, NY, 10019, USA
3 Department of Medicine, Columbia University, New York, NY 10032, USA
4 Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
5 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA
BMC Molecular Biology 2009, 10:37 doi:10.1186/1471-2199-10-37
Published: 5 May 2009Abstract
Background
Human sex hormone-binding globulin (SHBG) regulates free sex steroid concentrations in plasma and modulates rapid, membrane based steroid signaling. SHBG is encoded by an eight exon-long transcript whose expression is regulated by a downstream promoter (PL). The SHBG gene was previously shown to express a second major transcript of unknown function, derived from an upstream promoter (PT), and two minor transcripts.
Results
We report that transcriptional expression of the human SHBG gene is far more complex than previously described. PL and PT direct the expression of at least six independent transcripts each, resulting from alternative splicing of exons 4, 5, 6, and/or 7. We mapped two transcriptional start sites downstream of PL and PT, and present evidence for a third SHBG gene promoter (PN) within the neighboring FXR2 gene; PN regulates the expression of at least seven independent SHBG gene transcripts, each possessing a novel, 164-nt first exon (1N). Transcriptional expression patterns were generated for human prostate, breast, testis, liver, and brain, and the LNCaP, MCF-7, and HepG2 cell lines. Each expresses the SHBG transcript, albeit in varying abundance. Alternative splicing was more pronounced in the cancer cell lines. PL- PT- and PN-derived transcripts were most abundant in liver, testis, and prostate, respectively. Initial findings reveal the existence of a smaller immunoreactive SHBG species in LNCaP, MCF-7, and HepG2 cells.
Conclusion
These results extend our understanding of human SHBG gene transcription, and raise new and important questions regarding the role of novel alternatively spliced transcripts, their function in hormonally responsive tissues including the breast and prostate, and the role that aberrant SHBG gene expression may play in cancer.