Regulatory mechanisms of SoxD transcription factors and their influences on male fertility.

Members of the SRY-related box (SOX) subfamily D (SoxD) of transcription factors are well conserved among vertebrate species and play important roles in different stages of male reproductive development. In mammals, the SoxD subfamily contains three members: SOX5, SOX6 and SOX13. Here, we describe their implications in testicular development and spermatogenesis, contributing to fertility. We also cover the mechanisms of action of SoxD transcription factors in gene regulation throughout male development. The specificity of activation of target genes by SoxD members depends, in part, on their post-translational modifications and interactions with other partners. Sperm production in adult males requires the coordination in the regulation of gene expression by different members of the SoxD subfamily of transcription factors in the testis. Specifically, the regulation of genes promoting adequate spermatogenesis by SoxD members is discussed in comparison between species.

The transcription factors Creb1 and CEBPB regulate Sox9 promoter activity in TM4 Sertoli cells.

In Sertoli cells, the Sox9 gene is essential for testicular development and normal spermatogenesis. SOX9 is critical for postnatal Sertoli cells differentiation and proliferation in the testis. However, the molecular mechanisms that specifically regulate its expression are not entirely understood. Sox9 expression is regulated by CREB1 and CEBPB in other biological contexts such as during chondrogenesis and in rat thyroid follicular cells. We hypothesized that Sox9 promoter activity is regulated by CREB1 and CEBPB in Sertoli cells. Our results show that Sox9 expression is dependent on the activation of these transcription factors by the cAMP/PKA signaling pathway in TM4 Sertoli cells. Chromatin immunoprecipitation and promoter/reporter luciferase assays with 5' promoter deletions and site-directed mutagenesis demonstrated that CREB1 is being recruited to a DNA regulatory element at -141 bp of the Sox9 promoter region. Such regulation is dependent on the cAMP/PKA signaling pathway, resulting in phosphorylation of CREB1. Activation of Sox9 expression by CEBPB may involve its recruitment to the proximal promoter region by protein-protein interaction with CREB1. Thus, we have shown that the Sox9 promoter is being regulated by the transcription factors CREB1 and CEBPB in TM4 Sertoli cells and involve their recruitment to the proximal promoter region.

The Pro-Tumoral Activity of Heparan Sulfate 3-O-Sulfotransferase 3B (HS3ST3B) in Breast Cancer MDA-MB-231 Cells Is Dependent on the Expression of Neuropilin-1.

Heparan sulfate 3-O-sulfotransferases (HS3STs) catalyze the maturation step of heparan sulfate (HS) 3-O-sulfation. This modification is relatively rare. Moreover, only a few biological processes have been described to be influenced by 3-O-sulfated HS, and few ligands have been identified so far. Among them, neuropilin-1 (Nrp1) was reported to exhibit tumor-promoting properties by enhancing the action of various growth factors. We recently demonstrated that transient overexpression of HS3ST2, 3B or 4 enhanced the proliferation of breast cancer MDA-MB-231 cells and promote efficient protection against pro-apoptotic stimuli. Hence, we hypothesized that the pro-tumoral activity of these HS3STs could depend on the expression of Nrp1. To test this, MDA-MB-231 cells were stably transfected with a construct encoding HS3ST3B and the expression of Nrp1 was down-regulated by RNA interference. First, we confirmed that stable expression of HS3ST3B effectively increased cell proliferation and viability. Silencing the expression of Nrp1 markedly attenuated the promoting effects of HS3ST3B, while the same treatment had only a moderate effect on the behavior of the parental cells. Altogether, our findings support the idea that the tumor-promoting effects of HS3ST3B could be dependent on the expression of Nrp1 in cancer cells.