| First Author | Zhang C | Year | 2014 |
| Journal | Biochim Biophys Acta | Volume | 1839 |
| Issue | 11 | Pages | 1170-82 |
| PubMed ID | 25153068 | Mgi Jnum | J:218461 |
| Mgi Id | MGI:5617645 | Doi | 10.1016/j.bbagrm.2014.08.006 |
| Citation | Zhang C, et al. (2014) A chromatin modifier regulates Sertoli cell response to mono-(2-ethylhexyl) phthalate (MEHP) via tissue inhibitor of metalloproteinase 2 (TIMP2) signaling. Biochim Biophys Acta 1839(11):1170-82 |
| abstractText | Epigenetic silencing mechanisms are essential for regulating germ cell apoptosis in response to different stimuli during complicated spermatogenesis. Herein, we report the potential signaling events related to up-regulation of metastasis associated protein 1 (Mta1), a master chromatin modifier, during mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cells (SCs) injury. Mta1 up-regulation correlated to the gradual increases of MYC expression in MEHP-treated SCs. Selective knockdown of MYC abolished MEHP-induced activation of Mta1, suggesting that MYC may regulate the Mta1 signaling following MEHP injury. Furthermore, MTA1 acted as a specific corepressor of tissue inhibitor of metalloproteinase 2 (Timp2) during SCs injury. Mta1 repressed Timp2 expression either directly by recruiting histone deacetylase 2 onto the Timp2 promoter or indirectly by enhancing NF-kappaB-mediated inflammatory responses during MEHP injury. This transcriptional and post-translational down-regulation of Timp2/TIMP2 expression consequently resulted in the stimulated activation of matrix metalloproteinase 2 (MMP2) in SCs, which should ultimately promote germ cell death upon MEHP insult. From a functional standpoint, inhibition of endogenous Mta1 expression along with anti-inflammation treatment in cultured SCs could rescue MEHP-inhibited TIMP2 and subsequently rebalanced MMP2 activity to the control level. Together with the recently reported essential role of TIMP2/MMP2 signaling in MEHP-induced specific disruption of junctional complexes in the seminiferous epithelium, our results further substantiate a critical role of Mta1 in the control of SCs response to MEHP stimulation. The MYC/Mta1/TIMP2 circuit may serve as an important scavenger mechanism to help to maintain the capacity of damaged SCs to support germ cell development following MEHP injury. |
