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  • Interestingly ZIP expression was decreased in dog testes

    2024-04-03

    Interestingly, ZIP9 expression was decreased in dog testes after they were implanted with gonadotropin releasing hormone (GnRH) which the authors proposed was due to androgen ablation (Bulldan et al., 2016a). The expression of other members GDC0941 of the ZIP (SLC39A) family has also been shown to be regulated by hormones (Cousins et al., 2006; Table 1). For example, prolactin increases the expression of ZIP1 in two prostate cancer cell lines, LNCaP and PC-3 (Costello et al., 1999), while testosterone has been found to increase ZIP2 expression in the rat prostate (Iguchi et al., 2006). Hormonal regulation of ZIP expression is widespread and has been reported for half of the SLC39A family members (Table 1). These results suggest that hormonal regulation of physiological functions in target GDC0941 through alterations in the activity of zinc transporters and zinc signaling is a common endocrine mechanism that warrants more extensive investigation.
    Characteristics of human ZIP9 in breast and prostate cancer cells The investigation of shared characteristics of homologous novel proteins in distantly-related vertebrate groups is a powerful tool for determining their major, evolutionarily-conserved functions. The localization, steroid binding, signaling, and apoptotic functions of wildtype and recombinant human ZIP9 were investigated in nAR-null human breast cancer (MDA-MB-231 and MDA-MB-468) and prostate cancer (PC-3) cell models (Thomas et al., 2014). The results showed that human ZIP9 is expressed on the cell surface of these cancer cells and displays the same high affinity, specific T binding characteristics as those of croaker ZIP9. Treatment with T also activates a G protein through human ZIP9, but instead of activating a stimulatory G protein, an inhibitory G protein (Gi) is activated in the cancer cells. Moreover, human ZIP9 has the same androgen-specific zinc transport and proapoptotic functions as croaker ZIP9. T and DHT induce increases in intracellular free zinc and apoptosis, whereas nAR agonists and other steroids are ineffective (Thomas et al., 2014). Thus, although croaker ZIP9 and human ZIP9 are separated by approximately 400 million years of evolution from a common vertebrate ancestor they have retained the same T binding, and androgen-dependent signal transduction, zinc transport, and proapoptotic functions. The involvement of known members of proapoptotic pathways in T-induced apoptosis was investigated in human ZIP9-transfected PC-3 cells and in MDA-MB-468 cells expressing wild type ZIP9. T treatment increased the expression of Bax (Bcl-2-associated X protein) and p53 (tumor protein 53) genes, which are components of the intrinsic apoptotic pathway, and also JNK (c-Jun N-terminal kinases), which is involved in both the intrinsic and intrinsic apoptotic pathways (Thomas et al., 2014). These changes in gene expression were accompanied by T-induced increases in the concentrations of Bax, cytochrome C and Caspase 3 proteins as well as Caspase 3 activity. Collectively, these results indicate a plausible intrinsic pathway by which T induces apoptosis. A model has been proposed for the induction of apoptosis in these cancer cells by T acting through ZIP9 (Thomas et al., 2017).
    Characteristics of ZIP9 in other cells The results of recent studies by other research groups have supported a role of ZIP9 in nonclassical T signaling (Bulldan et al., 2016b, Shihan et al., 2015). T increases phosphorylation of ERK1/2, CREB and ATF-1 in a ZIP9-dependent manner in a nAR-null Sertoli cell line, 93RS2, resulting in increased expression of claudins that are essential constituents of tight junction formation and the maintenance of the blood-testis barrier (Bulldan et al., 2016b). Interestingly, T phosphorylates the same proteins in the spermatogenic GC-2 cell line through ZIP9 which is coupled to a Gq protein, Gnα11, (Shihan et al., 2015). Finally, upregulation of ZIP9 expression in gliobastoma cells increased phosphorylation of GSK-3β, which stimulated gliobastoma cell migration (Munnich et al., 2016). Thus, the limited studies conducted on ZIP9 to date suggest that it mediates a variety of functions in vertebrate cells.