Human Sex Hormone-binding Globulin is Expressed in Testicular Germ Cells and not in Sertoli Cells

Abstract

The human sex hormone-binding globulin (SHBG) gene contains at least two transcription units. A 4.3 kb human SHBG transcription unit encodes the precursor polypeptide, which is processed and secreted by hepatocytes as plasma SHBG. The proximal promoter of this transcription unit differs from the corresponding sequence in other mammals, in which it is also expressed in Sertoli cells. In particular, its proximal promoter sequence contains a binding site for USF transcription factors that represses its activity in Sertoli cells. Although human SHBG is not expressed in Sertoli cells, human SHBG transcripts containing an alternative exon 1 sequence are present in testicular germ cells. These are the products of an ∼ 8 kb human SHBG transcription unit, and they appear to encode an SHBG isoform that is 4 – 5 kDa smaller than plasma SHBG. This sperm SHBG isoform accumulates between the outer acrosomal membrane and the sperm plasma membrane, and it is released during the capacitation reaction. These remarkable differences in human SHBG expression in the testis, when compared to other mammals, force us to reconsider the functional significance of SHBG expression in the testis in relation to male reproduction.

Key words

Sperm - acrosome - androgen binding protein - spermatogenesis - transcription - testis - fertility - alternative transcripts - promoters - transgenic mice

References

• 1 Hammond G L. Potential functions of plasma steroid-binding proteins. Trends Endocrinol.  Metab. 1995;  6 298-304
• 2 French F S, Ritzen E M. A high-affinity androgen-binding protein (ABP) in rat testis: Evidence for secretion into efferent duct fluid and absorption by epididymis.  Endocrinology. 1973;  93 88-95
• 3 Danzo B J, Eller B C, Orgebin-Crist M-C. Studies on the site of origin of the androgen binding protein present in epididymal cytosol from mature intact rabbits.  Steroids. 2004;  24 107-122
• 4 Joseph D R. Structure, function, and regulation of androgen-binding protein/sex hormone-binding globulin.  Vit Horm. 1994;  49 197-280
• 5 Hammond G L, Underhill D A, Rykse H M, Smith C L. The human sex hormone-binding globulin gene contains exons for androgen-binding protein and two other testicular messenger RNAs.  Mol Endocrinol. 1989;  3 1869-1876
• 6 Westphal U. Steroid-Protein Interactions II. Monographs on Endocrinology. Springer Verlag Berlin; 1926 27: 198-301
• 7 Skinner M K, Schlitz S M, Anthony C T. Regulation of Sertoli cell differentiated function: Testicular transferrin and androgen-binding protein expression.  Endocrinology. 1989;  124 3024
• 8 Gunsalus G L, Musto N A, Bardin C W. Bidirectional release of a Sertoli cell product, androgen binding protein, into the blood and seminiferous tubule. In: Steinberger A, Steinberger E (eds) Testicular Development, Structure, and Function. New York; Raven Press 1980: 291-297
• 9 Pelliniemi L J, Dym M, Gunsalus G L, Musto N A, Bardin C W, Fawcett D W. Immunocytochemical localization of androgen-binding protein in the male rat reproductive tract.  Endocrinology. 1981;  108 925-931
• 10 Selva D M, Bassas L, Munell F, Mata A, Tekpetey F, Lewis J G, Hammond G L. Human Sperm Sex Hormone-binding Globulin Isoform: Characterization and Measurement by Time-resolved Fluorescence Immunoassay.  Journal of Clinical Endocrinology and Metabolism. 2005;  90 6275-6282
• 11 Santiemma V, Rosati P, Guerzoni C, Mariani S, Beligotti F, Magnanti M, Garufi G, Galoni T, Fabbrini A. Human Sertoli cells in vitro: Morphological features and androgen-binding protein secretion. J.  Steroid Biochem Mol Biol. 1992;  43 423-429
• 12 Joseph D R, Hall S H, French F S. Rat androgen-binding protein: Evidence for identical subunits and amino acid sequence homology with human sex hormone-binding globulin.  Proc Natl Acad Sci USA. 1987;  84 339-343
• 13 Joseph D R, Hall S H, Conti M, French F S. The gene structure of rat androgen-binding protein: Identification of potential regulatory deoxyribonucleic acid elements of a follicle-stimulating hormone-regulated protein.  Mol Endocrinol. 1988;  2 3-13
• 14 Reventos J, Hammond G L, Crozat A, Brooks D E, Gunsalus G L, Bardin C W, Musto N A. Hormonal regulation of rat androgen-binding protein (ABP) messenger ribonucleic acid and homology of human testosterone-estradiol-binding globulin and ABP complementary deoxyribonucleic acids.  Mol Endocrinol. 1988;  2 125-132
• 15 Reventos J, Sullivan P M, Joseph D R, Gordon J W. Tissue-specific expression of the rat androgen-binding protein/sex hormone-binding globulin gene in transgenic mice.  Mol Cell Endocrinol. 1993;  96 69-73
• 16 Jänne M, Deol H K, Power S GA, Yee S-P, Hammond G L. Human sex hormone-binding globulin gene expression in transgenic mice.  Mol Endocrinol. 1998;  12 123-136
• 17 Selva D M, Hogeveen K N, Seguchi K, Tekpetey F, Hammond G L. A human sex hormone-binding globulin isoform accumulates in the acrosome during spermatogenesis.  J Biol Chem. 2002;  277 45 291-45 298
• 18 Jänne M, Hammond G L. Hepatocyte nuclear factor-4 controls transcription from a TATA-less human sex hormone-binding globulin gene promoter.  J Biol Chem. 1998;  273 34 105-34 114
• 19 Selva D M, Hogeveen K N, Hammond G L. Repression of the human sex hormone-binding globulin gene in Sertoli cells by USF transcription factors.  J Biol Chem. 2005;  280 4462-4468
• 20 Hsu S H, Hsieh-Li H M, Li H. Dysfunctional spermatogenesis in transgenic mice overexpressing bHLH-Zip transcription factor, Spz1.  Experimental Cell Research. 2004;  294 185-198
• 21 Don J, Stelzer G. The expanding family of CREB/CREM transcription factors that are involved with spermatogenesis.  Molecular and Cellular Endocrinology. 2002;  187 115-124
• 22 Hogeveen K N, Cousin P, Pugeat M, Dewailly D, Soudan B, Hammond G L. Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction.  J Clin Invest. 2002;  109 973-981
• 23 Luconi M, Muratori M, Forti G, Baldi E. Identification and characterization of a novel functional estrogen receptor on human sperm membrane that interferes with progesterone effects.  J Clin Endocrinol Metab. 1999;  84 1670-1678
• 24 Luconi M, Francavilla F, Porazzi I, Macerola B, Forti G, Baldi E. Human spermatozoa as a model for studying membrane receptors mediating rapid nongenomic effects of progesterone and estrogens.  Steroids. 2004;  69 553-559
• 25 Smithwick E B, Young R A. Germ cell maturation and cellular associations in the seminiferous epithelial cycle of the chimpanzee.  Tissue Cell. 1996;  28 137-148
• 26 Grishkovskaya I, Avvakumov G V, Sklenar G, Dales D, Hammond G L, Muller Y A. Crystal structure of human sex hormone-binding globulin: Steroid transport by a laminin G-like domain.  EMBO J. 2000;  19 504-512