Date of Award


Degree Type


Degree Name

Doctor of Philosophy


Sex-hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) are the major plasma transport proteins for sex-steroids and glucocorticoids, respectively, and may impact directly upon steroid hormone bioavailability to target cells. Androgen binding protein (ABP) is closely related to SHBG and is believed to maintain an androgenic environment for sperm maturation. The isolation of SHBG-related cDNAs from human testis and a corresponding transcription unit indicates that SHBG and ABP are encoded by the same gene. In addition, the SHBG/ABP gene gives rise to two novel testicular transcripts through a process of alternative splicing. The putative proteins encoded by these transcripts are related to SHBG, but contain differences that may specify unique functions. Interestingly, the human SHBG/ABP gene contains multiple Alu repetitive elements, and one of these was implicated in the process of alternative splicing. It is clear that CBG is a member of the serine proteinase inhibitor superfamily, and is closely related to {dollar}\alpha{dollar}1-proteinase inhibitor ({dollar}\alpha{dollar}1-PI). The human CBG gene was isolated and found to comprise five exons distributed over an approximately 19 kb region of the human genome, and the finding that it has the same exon/intron structure as the {dollar}\alpha{dollar}1-PI gene indicates that they have arisen by a recent gene duplication event. Studies of the regulation of CBG gene expression were extended with the characterization of the rat CBG gene promoter. Five protein binding sites were identified in the rat CBG gene promoter that were closely related to known transcription factor binding elements. Notably, the rat CBG gene promoter contains a binding site for hepatocyte nuclear factor-1 (HNF-1). Transient transfection of rat CBG gene promoter deletion constructs into H4IIEC3 cells revealed the presence of both positive and negative-acting cis-elements, and that promoter function was serum-dependent. In addition, the rat CBG gene promoter contains cis-element(s) that potently repress its activity in HeLa cells. The continued study of the SHBG/ABP and CBG genes should precisely define their regulation during biological processes, and may impact upon our understanding of eukaryotic gene expression in general.



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