Apoptosis Induced by Transforming Growth Factor-β in Fetal Hepatocyte Primary Cultures

Sánchez, Aránzazu; Álvarez, Alberto; Benito, Manuel; Fabregat, Isabel

doi:10.1074/jbc.271.13.7416

Cited by 261 publications

(228 citation statements)

References 51 publications

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“…Preparation of nuclear extracts from livers and sorted cell populations was performed as described. 21,22 Protein concentration was measured by the Bio-Rad protein reagent following the recommendations of the supplier. For EMSA, 5 g of nuclear protein were mixed with 0.5 ng of radiolabeled oligonucleotide and 1 g poly (dI-dC) as nonspecific DNA competitor and incubated for 30 minutes at 4°C in binding buffer containing 10 mM HEPES, pH 7.9, 50 mM NaCl, 1 mM ethylenediaminetetraacetic acid, and 10% glycerol.…”

Section: Methodsmentioning

confidence: 99%

Activation of NF-κB and STAT3 in rat oval cells during 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration

et al. 2004

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Proliferation and differentiation of hepatic stem cell progenies (i.e., oval cells) sustain liver regeneration when the replicative and functional capacity of hepatocytes is impaired. The signaling pathways that control stem cell activation remain poorly understood. In this study, we investigated the involvement of nuclear factor-kappa B (NF-B) and signal transducer and activator of transcription 3 (STAT3) in oval cell-mediated liver regeneration induced by 2-acetylaminofluorene/partial hepatectomy (AAF/PH) protocol. Using OV1 as a marker for identification and sorting of oval cells, we established that both NF-B and STAT3 were highly activated in the OV1 ؉ cell population. Three distinct subpopulations of oval cells were defined as OV1 low , OV1 medium , and OV1 high , based on the intensity of OV1 staining. Quantitative polymerase chain reaction analysis revealed that they represent different stages of oval cell differentiation along hepatocyte lineage. OV1 low cells displayed the least differentiated phenotype as judged by high expression of c-kit and lack of hepatocytic differentiation markers, whereas OV1 high cells lost c-kit expression, were more proliferative, and acquired more mature hepatocytic phenotype. Notably, NF-B was activated uniformly in all three subpopulations of oval cells. In contrast, phosphorylation of STAT3 was detected only in OV1 high cells. In conclusion, transcriptional activity supported by NF-B and STAT3 is required for oval cell activation, expansion, and differentiation. The differential induction of NF-B and STAT3 point to a distinct role for these transcription factors at different stages of hepatic stem cell differentiation. (HEPATOLOGY 2004;39:376 -385.)

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Section: Methodsmentioning

confidence: 99%

Activation of NF-κB and STAT3 in rat oval cells during 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration

et al. 2004

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“…Analysis of cell number. Cell number was analyzed after crystal violet staining (0.2% in 2% ethanol), as previously described [10].…”

Section: Page 5 Of 27mentioning

confidence: 99%

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

Sancho

Fabregat

2011

Biochemical Pharmacology

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This compound inhibits dose-dependently autocrine increase of cell number in FaO rat hepatoma cells, and almost completely blocked ROS production and thymidine incorporation when used at 25 M. Such inhibitory effect on autocrine growth is coincident with lower mRNA levels of EGFR (Epidermal Growth Factor Receptor) and its ligand TGF-(Transforming Growth Factor-alpha), and decreased phosphorylation of the EGFR itself and other downstream targets, such as SRC or AKT. Moreover, NADPH oxidase pharmacological inhibition also effectively attenuates serum-dependent growth and phosphorylation of AKT and ERK. Importantly, these inhibitory effects on either autocrine or serum-dependent cell growth are observed in several human HCC cell lines. Finally, we have observed that VAS2870 is also effective in enhancing apoptosis induced by a physiological stimulus, such as TGF-. In summary, NADPH oxidase pharmacological inhibition could be considered a promising tool in the treatment of liver cancer.

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“…We did not measure apoptosis directly; however, we used concentrations of TGF-␤ an order of magnitude less than those previously reported to induce apoptosis in hepatocytes. 51,52 The lack of any effect of TGF-␤ on basal kinase activities or on the EGF-induced stimulation of PKB also argues against the induction of apoptosis, particularly because PKB is considered to protect cells from apoptosisinducing stimuli. 53,54 At least three lines of evidence support the hypothesis that the inhibition of EGF-induced activation of ERK and p70 S6k by TGF-␤ and glucagon plays a role in their inhibitory effects on hepatocyte proliferation.…”

Section: Fig 3 Tgf-␤ and Glucagon Do Not Inhibit Egf-induced Jnk1 Omentioning

confidence: 99%

Inhibition of Rat Hepatocyte Proliferation by Transforming Growth Factor β and Glucagon Is Associated With Inhibition of Erk2 and P70 S6 Kinase

Dixon¹,

Agius²,

Yeaman

et al. 1999

Hepatology

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Stimulation of hepatocyte proliferation by epidermal growth factor (EGF) and insulin is inhibited by transforming growth factor ␤ (TGF-␤) and by glucagon. It is also suppressed by inhibitors of various protein kinases, including rapamycin, which blocks activation of p70 S6 kinase (p70 S6k ), PD98059, which inhibits the activation of extracellular-regulated kinase (ERK), and SB 203580, an inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK). In this study, we investigated whether the inhibition of proliferation by TGF-␤ involves these protein kinase cascades. Culture of hepatocytes with TGF-␤ for 16 hours decreased the stimulation by EGF of ERK2 and p70 S6k (by 50% and 35%, respectively), but did not affect the stimulation of either p38 MAPK, c-jun NH 2 -terminal kinase (JNK), or protein kinase B (PKB). Culture of hepatocytes with glucagon for 16 hours also inhibited the stimulation by EGF of activation of ERK2 and p70 S6k (by E50%). The inhibitory effects of glucagon were observed when the hormone was added either 10 minutes or 60 minutes before EGF addition, whereas no effects of TGF-␤ were observed after 10-minute or 60-minute incubation. These results suggest that the inhibition of hepatocyte proliferation by TGF-␤ may be in part mediated by inhibition of ERK2 and p70 S6k , but does not involve PKB, JNK, or p38 MAPK. Unlike glucagon, the effects of TGF-␤ are not elicited in response to short-term treatment. (HEPATOLOGY 1999;29:1418-1424 Hepatocyte proliferation following injury or partial hepatectomy is regulated by the action of both stimulatory (mitogenic) and inhibitory growth factors and hormones (reviewed in Michalopoulos 1 and Fausto 2 ). Studies in primary hepatocyte cultures have identified several complete mitogens capable of inducing DNA synthesis in serum-free medium,

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Apoptosis Induced by Transforming Growth Factor-β in Fetal Hepatocyte Primary Cultures

Cited by 261 publications

References 51 publications

Activation of NF-κB and STAT3 in rat oval cells during 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration

Activation of NF-κB and STAT3 in rat oval cells during 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

Inhibition of Rat Hepatocyte Proliferation by Transforming Growth Factor β and Glucagon Is Associated With Inhibition of Erk2 and P70 S6 Kinase

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