Transforming Growth Factor-β1 is Responsible for Maturation-Dependent Spontaneous Apoptosis of Cultured Gastric Pit Cells

Tsutsumi, Shinji; Tomisato, Wataru; Hoshino, Tatsuya; Tsuchiya, Tomofusa; Mizushima, Tohru

doi:10.1177/153537020222700606

Cited by 15 publications

(8 citation statements)

References 45 publications

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“…In these conditions, we assessed the role of extrinsic stimuli on EVER2 pro-apoptotic effects. Tsutsumi et al 14 used a similar procedure for assessing the pro-apoptotic effect of TGF- β in serum. In conditions of FCS deprivation (0.2% FCS), we almost totally abrogated EVER2 effects on cell death even at high concentrations, suggesting that EVER2-induced cell death was mainly triggered by extrinsic factors activating cell surface receptors (Figure 1b).…”

Section: Resultsmentioning

confidence: 99%

EVER2 protein binds TRADD to promote TNF-α-induced apoptosis

et al. 2013

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EVER1 and 2 confer resistance to cutaneous oncogenic human papillomavirus infections by downregulating the activating protein 1 (AP-1) signaling pathway. Defects in their expression are associated with susceptibility to epidermodysplasia verruciformis, which is characterized by persistent β-HPV infection, tumor necrosis factor alpha (TNF-α) overproduction in keratinocytes and the development of skin cancers. TNF-α-induced apoptosis is a key defense strategy, preventing the persistence of the virus within cells, but the role of EVER proteins in this cell death mechanism triggered by extrinsic stimuli is unknown. We show here that EVER2 induces TNF-α- and TRAIL-dependant apoptosis. It interacts with the N-terminal domain of TRADD, impairs the recruitment of TRAF2 and RIPK1 and promotes apoptosis. The skin cancer-associated EVER2 I306 allele results in an impaired TRADD–EVER2 interaction, with lower levels of cell death following treatment with TNF-α. These data highlight a new, critical function of EVER2 in controlling cell survival in response to death stimuli.

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Section: Resultsmentioning

confidence: 99%

EVER2 protein binds TRADD to promote TNF-α-induced apoptosis

et al. 2013

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“…The inhibitor is released on exposure of intestinal tissue to radiation and likely to other oxidative stimuli, leading to increased apoptosis and probably other defensive responses (Thavaraj et al 2005). TGF-β also regulates growth and apoptosis in other contexts (Arsura et al 2003), including development (Tsutsumi et al 2002). …”

Section: What Is the Mechanism And Consequence Of Interactive Effects?mentioning

confidence: 99%

Assessing Cumulative Health Risks from Exposure to Environmental Mixtures—Three Fundamental Questions

Sexton

Hattis

2007

Environ Health Perspect

138

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Differential exposure to mixtures of environmental agents, including biological, chemical, physical, and psychosocial stressors, can contribute to increased vulnerability of human populations and ecologic systems. Cumulative risk assessment is a tool for organizing and analyzing information to evaluate the probability and seriousness of harmful effects caused by either simultaneous and/or sequential exposure to multiple environmental stressors. In this article we focus on elucidating key challenges that must be addressed to determine whether and to what degree differential exposure to environmental mixtures contributes to increased vulnerability of exposed populations. In particular, the emphasis is on examining three fundamental and interrelated questions that must be addressed as part of the process to assess cumulative risk: a) Which mixtures are most important from a public health perspective? and b) What is the nature (i.e., duration, frequency, timing) and magnitude (i.e., exposure concentration and dose) of relevant cumulative exposures for the population of interest? c) What is the mechanism (e.g., toxicokinetic or toxicodynamic) and consequence (e.g., additive, less than additive, more than additive) of the mixture’s interactive effects on exposed populations? The focus is primarily on human health effects from chemical mixtures, and the goal is to reinforce the need for improved assessment of cumulative exposure and better understanding of the biological mechanisms that determine toxicologic interactions among mixture constituents.

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“…In the gastrointestinal tract, TGFβ isoforms regulate epithelial renewal through effects on cell proliferation [3]–[7], differentiation [8], [9], epithelial mesenchymal transition [10], [11], migration [12], and apoptosis [13]. TGFβ has been detected in human and murine milk [14], [15] and after suckling and oral administration, signaling is activated in gastric epithelial cells through receptors (TβRI and TβRII) and Smads central cascade [6], [15]–[17].…”

Section: Introductionmentioning

confidence: 99%

Transforming Growth Factor β1 Increases p27 Levels via Synthesis and Degradation Mechanisms in the Hyperproliferative Gastric Epithelium in Rats

2014

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Throughout postnatal development, the gastric epithelium expresses Transforming Growth Factor beta1 (TGFβ1), but it is also exposed to luminal peptides that are part of milk. During suckling period, fasting promotes the withdrawal of milk-born molecules while it stimulates gastric epithelial cell proliferation. Such response can be reversed by exogenous TGFβ1, as it directly affects cell cycle through the regulation of p27 levels. We used fasting condition to induce the hyperproliferation of gastric epithelial cells in 14-day-old Wistar rats, and evaluated the effects of TGFβ1 gavage on p27 expression, phosphorylation at threonine 187 (phospho-p27Thr187) and degradation. p27 protein level was reduced during fasting when compared to suckling counterparts, while phospho-p27Thr187/p27 ratio was increased. TGFβ1 gavage reversed this response, which was confirmed through immunostaining. By using a neutralizing antibody against TGFβ1, we found that it restored the p27 and phosphorylation levels detected during fasting, indicating the specific role of the growth factor. We noted that neither fasting nor TGFβ1 changed p27 expression, but after cycloheximide administration, we observed that protein synthesis was influenced by TGFβ1. Next, we evaluated the capacity of the gastric mucosa to degrade p27 and we recorded a higher concentration of the remaining protein in pups treated with TGFβ1, suggesting augmented stability under this condition. Thus, we showed for the first time that luminal TGFβ1 increased p27 levels in the rat gastric mucosa by up- regulating translation and reducing protein degradation. We concluded that such mechanisms might be used by rapidly proliferating cells to respond to milk-born TGFβ1 and food restriction.

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Transforming Growth Factor-β1 is Responsible for Maturation-Dependent Spontaneous Apoptosis of Cultured Gastric Pit Cells

Cited by 15 publications

References 45 publications

EVER2 protein binds TRADD to promote TNF-α-induced apoptosis

EVER2 protein binds TRADD to promote TNF-α-induced apoptosis

Assessing Cumulative Health Risks from Exposure to Environmental Mixtures—Three Fundamental Questions

Transforming Growth Factor β1 Increases p27 Levels via Synthesis and Degradation Mechanisms in the Hyperproliferative Gastric Epithelium in Rats

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