The bcl, NFκB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-β or TNF-α on activated hepatic stellate cells

Saile, Bernhard; Matthes, Nina; Armouche, Hammoudeh El; Neubauer, Katrin; Ramadori, Giuliano

doi:10.1078/0171-9335-00182

Cited by 133 publications

(99 citation statements)

References 37 publications

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“…Unexpectedly, activated TGF-b attenuated HUVEC apoptosis. Although this observation is in line with several reports on the protective effect of TGF-b against apoptosis of cells other than HUVECs, 40,[49][50][51][52][53] our observations are not in complete accordance with the findings on the apoptosis-inducing effect of recombinant TGFb1 on bovine capillary endothelial cells. 5 While attempting to reproduce those findings, we observed that HUVECs were markedly resistant to TGF-b1-induced apoptosis (results not shown), consistent with observations by others.…”

Section: Discussioncontrasting

confidence: 59%

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

Solovyan

Keski‐Oja

2005

Cell Death Differ

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Transforming growth factors b (TGF-bs) are multifunctional cytokines that modulate cell growth, differentiation and apoptosis. Numerous effects initiated by TGF-bs in vitro have been described, but the role of TGF-b targeting and activation under physiological conditions has gained very little attention and understanding. We report here that apoptosis of human umbilical vein endothelial cells (HUVECs) is accompanied by release of truncated large latent TGF-b complexes from the pericellular matrix followed by activation of TGF-b. The activation of TGF-b during apoptosis was accompanied by enhanced secretion of b1-LAP protein, and apoptotic HUVECs acquired the capacity to induce the release of latent TGF-bbinding proteins (LTBPs) from extracellular matrices. Activated TGF-b, in turn, attenuated apoptotic death of HUVECs. Current results indicate that the activation of TGF-b accompanies the apoptosis of HUVECs, and may play a protective feedback role against apoptotic cell death. The results suggest a role for TGF-b as a putative extracellular modulator of apoptosis.

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Section: Discussioncontrasting

confidence: 59%

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

Solovyan

Keski‐Oja

2005

Cell Death Differ

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“…The best studied exception to this observation occurs in tumor cells in which various alterations in the TGF-β signaling pathway allows for escape from the pro-apoptotic effects of TGF-β. TGF-β has been shown to promote neuronal cell survival by stimulation and activation of ALK1, an alternate TGF-β receptor, resulting in activation and phosphorylation of SMADs 1 and 5 (data not shown) [50][51][52]. In studies of Konig et al [18], TGF-β stimulated neuronal cell ALK1, but not ALK5/ TβRI, expression within one hour of TGF-β treatment.…”

Section: Discussionmentioning

confidence: 84%

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

Gingery

Bradley

Pederson

et al. 2008

Experimental Cell Research

163

120

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To better understand the roles of TGF-β in bone metabolism, we investigated osteoclast survival in response TGF-β and found that TGF-β inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-β receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-β treatment. Since osteoclast survival involves MEK, AKT, and NFκB activation, we examined TGF-β effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, IκB, and NFκB. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NFκB activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NFκB repressed TGF-β-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-β-mediated kinase pathway activation and constitutively active AKT expression overcame apoptosis induction following MEK inhibition. TAK1/MEK activation induces pro-survival BclX L expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-β-induced NFκB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-β to support of osteoclast survival.

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“…However, high levels of I B␣ prevent TNF-␣ from activating NF-B. As a result, the induction of some NF-B targets, such as the cell signaling molecule cyclin D1 25 and hepatoprotective factor Bcl-xL, 40 but not the IL-6/STAT3 pathway, is impaired. The end result is decreased hepatocyte proliferation and increased apoptotic liver cell death, ultimately impeding liver regeneration in these mice.…”

Section: Discussionmentioning

confidence: 99%

A High-Fat Diet Impairs Liver Regeneration in C57BL/6 Mice Through Overexpression of the NF-κB Inhibitor, IκBα * #

et al. 2005

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Despite the growing incidence of obesity, knowledge of how this condition, as well as associated steatosis, affects liver regeneration remains scarce. Many previous studies have used models of steatohepatitis or obesity induced by genetic alterations. In contrast, our studies on liver regeneration have focused on the effects of obesity resulting solely from high amounts of fat in the diet. This model more closely reflects the detrimental effects of dietary habits responsible for increased morbidity due to obesity and its complications in welldeveloped Western societies. Impairment of liver regeneration was observed after partial hepatectomy in mice fed a high-fat diet. Fatty livers were more susceptible to posthepatectomy damage and failure. The underlying molecular mechanism was associated with increased inhibitor of nuclear factor-kappa B alpha (I B␣) expression, which inhibited nuclear factor-kappa B (NF-B) activation and induction of its target genes, cyclin D1 and Bcl-xL, increasing sensitivity to apoptosis initiated by elevated tumor necrosis factor-alpha. In addition, since mice fed with a high-fat diet have higher leptin levels caused by increased adiposity, our work supports the hypothesis that the impairment of regeneration previously seen in genetically obese mice indeed results from liver steatosis rather than the disruption of leptin signaling. In conclusion, high fat in the diet impairs liver regeneration and predisposes steatotic livers to increased injury through I B␣ overexpression and subsequent NF-B inhibition.

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The bcl, NFκB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-β or TNF-α on activated hepatic stellate cells

Cited by 133 publications

References 37 publications

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

A High-Fat Diet Impairs Liver Regeneration in C57BL/6 Mice Through Overexpression of the NF-κB Inhibitor, IκBα * #

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