Testicular germ cell sensitivity to TRAIL-induced apoptosis is dependent upon p53 expression and is synergistically enhanced by DR5 agonistic antibody treatment

McKee, Chad M.; Yang, Ye; Richburg, John H.

doi:10.1007/s10495-006-0288-1

Cited by 36 publications

(24 citation statements)

References 51 publications

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“…Importantly, even in rodents, DR5 is a major determinant of germ cell death upon DNA damage to testes. 59,60 This argues that the inducibility by p53 is the evolutionary older mechanism to enhance DR5 levels in testes. Only later, when Hominoids evolved, the insertion of the ERV9-LTR added an even more efficient mechanism to keep up the levels of DR5 in the male germline, thereby enhancing genomic surveillance in these cells.…”

Section: Catarrhinimentioning

confidence: 99%

Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death

Beyer

Krönung

Leha³

et al. 2015

Cell Death Differ

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The long terminal repeat (LTR) of human endogenous retrovirus type 9 (ERV9) acts as a germline-specific promoter that induces the expression of a proapoptotic isoform of the tumor suppressor homologue p63, GTAp63, in male germline cells. Testicular cancer cells silence this promoter, but inhibitors of histone deacetylases (HDACs) restore GTAp63 expression and give rise to apoptosis. We show here that numerous additional transcripts throughout the genome are driven by related ERV9-LTRs. 3' Rapid amplification of cDNA ends (3'RACE) was combined with next-generation sequencing to establish a large set of such mRNAs. HDAC inhibitors induce these ERV9-LTR-driven genes but not the LTRs from other ERVs. In particular, a transcript encoding the death receptor DR5 originates from an ERV9-LTR inserted upstream of the protein coding regions of the TNFRSF10B gene, and it shows an expression pattern similar to GTAp63. When treating testicular cancer cells with HDAC inhibitors as well as the death ligand TNF-related apoptosis-inducing ligand (TRAIL), rapid cell death was observed, which depended on TNFRSF10B expression. HDAC inhibitors also cooperate with cisplatin (cDDP) to promote apoptosis in testicular cancer cells. ERV9-LTRs not only drive a large set of human transcripts, but a subset of them acts in a proapoptotic manner. We propose that this avoids the survival of damaged germ cells. HDAC inhibition represents a strategy of restoring the expression of a class of ERV9-LTR-mediated genes in testicular cancer cells, thereby re-enabling tumor suppression.

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Section: Catarrhinimentioning

confidence: 99%

Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death

Beyer

Krönung

Leha³

et al. 2015

Cell Death Differ

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“…have been shown to induce apoptosis and senescence in the reproductive tract of rodents through p53 induction (Parmar et al, 1995;McKee et al, 2006). Di(2-ethylhexyl)phthalate (DEHP), a phthalate derivative and a well-known peroxisome proliferator (PP), is widely used as a plasticizer in the manufacture of PVC plastics.…”

Section: Introductionmentioning

confidence: 99%

Induction of ROS, p53, p21 in DEHP- and MEHP-exposed LNCaP cells-protection by selenium compounds

Erkekoğlu

Rachidi

Yuzugullu

et al. 2011

Food and Chemical Toxicology

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Keywords: DEHP MEHP p53 p21 ROS Selenium a b s t r a c t This study was designed to investigate the hypothesis that the toxic effects of di(2-ethylhexyl)phthalate (DEHP), the most abundantly used plasticizer and ubiquitous environmental contaminant that cause alterations in endocrine and spermatogenic functions in animals is mediated through the induction of reactive oxygen species (ROS) and activation of nuclear p53 and p21 proteins in LNCaP human prostate adenocarcinoma cell line. Protective effects of two selenocompounds, sodium selenite (SS) and selenomethionine (SM) were also examined. It was demonstrated that 24 h exposure of the cells to 3 mM DEHP or its main metabolite, mono(2-ethylhexyl)phthalate (MEHP, 3 lM) caused strongly amplified production of ROS. Both SS (30 nM) and SM (10 lM) supplementations reduced ROS production, and p53 and p21 activation that induced significantly only by MEHP-exposure. The overall results of this study indicated that the induction of oxidative stress is one of the important mechanisms underlying the toxicity of DEHP and this is mainly through the effects of the metabolite, MEHP. Generated data also emphasized the critical role of Se in modulation of intracellular redox status, implicating the importance of the appropriate Se status in cellular response against testicular toxicity of phthalates.

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“…They first focused on the germ cell apoptotic mechanism by demonstrating that the FAS signaling pathway is crucial for the initiation of germ cell apoptosis after MEHPinduced Sertoli cell injury, with Sertoli cells expressing the FAS ligand (FASL) and germ cells its receptor, FAS [19,[22][23][24][25][26]. Spermatocyte apoptosis also involves the increase of TRP53 stability and activity of the TRAIL/DR5 (official symbol TNFRSF10B) pathway [23,24,27,28]. In Sertoli cells, Yao et al [29] dissected the transcriptional regulation of FASL in response to MEHP.…”

Section: Mechanisms Of Action Of Phthalates On Seminiferous Epitheliumentioning

confidence: 99%

Dissecting the Phthalate-Induced Sertoli Cell Injury: The Fragile Balance of Proteases and Their Inhibitors1

Mazaud-Guittot¹

2011

Biology of Reproduction

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Spermatogenesis is a dynamic, finely hormonally regulated, and strictly spatially organized process by which spermatogonia divide, develop, and differentiate into spermatozoa. Spermatogenesis relies on two apparently opposite processes: the maintenance of the integrity of the seminiferous epithelium and the movement of germ cells from its base to its apex. Maintenance of the architectural integrity that is fundamental for spermatogenesis is ensured by three checkpoints: the seminiferous tubule basement membrane; the inter-Sertoli cell blood-testis barrier (BTB), sometimes more accurately referred to as the blood-seminiferous tubule barrier; and ectoplasmic specializations (ES) between Sertoli and differentiating germ cells. The BTB divides the seminiferous epithelium into two compartments: the basal compartment, which forms the niche for spermatogonial proliferation and renewal and the initiation of meiosis, and the adlumenal compartment, where meiosis is completed and spermiogenesis occurs. The migration of germ cells across the BTB as well as their release in the lumen relies on disassembly and reassembly of junctional components. Progress has been made on understanding the nature of proteases and their inhibitors involved in these processes and the regulations that finely tune this homeostasis [1][2][3][4][5]. With respect to proteases expressed in the testis, the matrix metalloproteinase (MMP) 2/MMP14/tissue inhibitor of metalloproteinase (TIMP) 2 system has emerged as crucial in apical ES dynamics [3,4,6]. The MMP2/TIMP2 homeostasis is fragile and was previously reported to be sensitive to phthalate [7]. In the current issue of Biology of Reproduction, Yao et al.[8] explore the transcriptional mechanism of Timp2 downregulation that follows phthalate exposure.

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Testicular germ cell sensitivity to TRAIL-induced apoptosis is dependent upon p53 expression and is synergistically enhanced by DR5 agonistic antibody treatment

Cited by 36 publications

References 51 publications

Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death

Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death

Induction of ROS, p53, p21 in DEHP- and MEHP-exposed LNCaP cells-protection by selenium compounds

Dissecting the Phthalate-Induced Sertoli Cell Injury: The Fragile Balance of Proteases and Their Inhibitors1

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