Activin induces cell death in hepatocytes in vivo and in vitro

Schwall, Ralph; Robbins, Kim; Jardieu, Paula; Chang, Ling; La, Cora; Terrel, Timothy G.

doi:10.1016/0270-9139(93)90018-i

Cited by 124 publications

(93 citation statements)

References 23 publications

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“…However, recombinant activin A treatment in combination with CCl 4 for 3 wk only modestly reduced the increase in proliferating hepatocytes observed in EC-KLF2-deficient mice, and cell death was not affected. These findings suggest that activin A preferentially affects hepatocyte proliferation, which is in line with the biological effect of activin A on DNA synthesis (25,26). Of note, addition of recombinant activin A only partially reversed the phenotype of EC-KLF2-deficient mice, suggesting that other factors contribute to the observed phenotype.…”

Section: Discussionsupporting

confidence: 64%

Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A

Manavski

Abel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Endothelial cells (ECs) not only are important for oxygen delivery but also act as a paracrine source for signals that determine the balance between tissue regeneration and fibrosis. Here we show that genetic inactivation of flow-induced transcription factor Krüppel-like factor 2 (KLF2) in ECs results in reduced liver damage and augmentation of hepatocyte proliferation after chronic liver injury by treatment with carbon tetrachloride (CCl4). Serum levels of GLDH3 and ALT were significantly reduced in CCl4-treated EC-specific KLF2-deficient mice. In contrast, transgenic overexpression of KLF2 in liver sinusoidal ECs reduced hepatocyte proliferation. KLF2 induced activin A expression and secretion from endothelial cells in vitro and in vivo, which inhibited hepatocyte proliferation. However, loss or gain of KLF2 expression did not change capillary density and liver fibrosis, but significantly affected hepatocyte proliferation. Taken together, the data demonstrate that KLF2 induces an antiproliferative secretome, including activin A, which attenuates liver regeneration.

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Section: Discussionsupporting

confidence: 64%

Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A

Manavski

Abel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…29 The growth factor TGF-B 1 and the related growth factor activin have been used in a number of studies to induce hepatocyte apoptosis in vivo and in vitro. [30][31][32][33] Antibodies against the surface antigen fas/APO-1 have also been successful in inducing apoptosis. 34 In other in vivo studies, researchers have treated rats with the liver mitogen cyproterone acetate to artificially increase liver cell number, and then have studied apoptosis in the regressing liver after mitogen withdrawal.…”

Section: Discussionmentioning

confidence: 99%

The Translational Inhibitor Cycloheximide Represses Growth Factor Depletion–Induced Apoptosis in An Alb–Sv40t Transgenic Rat Liver Cell Line

1996

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A transgenic rat line carrying the alb-SV40A of apoptosis. Described as a counterpart of mitosis, transgene has been described by this laboratory. Several apoptosis has been the focus of a large number of studcell lines have been established from the livers of two of ies since it was first described by Kerr et al. [1][2][3][4][5][6] Affecting these rats. One of these cell lines, L37, exhibits a large single or small groups of cells, apoptosis exhibits nuclear/cytoplasmic ratio and a well-differentiated cyto-changes in cellular ultrastructure that are distinct plasm containing numerous organelles. When L37 cells from the process of necrosis. 7,8 One of the first ultraare placed into culture medium lacking necessary structural changes observed in the apoptotic process is growth factors, cellular proliferation continues for 48 the shrinkage and detachment of apoptotic cells from with the dilation and vesiculation of the endoplasmic cent cells, eventually sloughing off the culture plate surface, with most cell deaths occurring between 48 and 96 reticulum 9 ; this forces intracellular fluids and ions out hours after medium change. Microscopic examination of of the cytoplasm. 10 Endoplasmic reticulum vesicles fuse sloughing cells indicates they possess highly convoluted with the plasma membrane, resulting in a highly conand blebbed plasma membranes, a morphological char-voluted and blebbed plasma membrane. 11 In addition, acteristic of apoptosis. Ultrastructural studies demon-there is a loss of plasma membrane functions, including strate the ubiquitous presence of apoptotic bodies. When loss of cell junctions and surface microvilli. Concurrent DNA isolated from growth factor-depleted cells is re-with the changes occurring in the endoplasmic reticusolved on agarose gels, DNA fragmentation ladders are lum, cytoplasm, and plasma membrane, nuclear events observed at times of maximum apoptotic change. Quanlead to the condensation and margination of the chrotitative analysis of L37 cells between 48 and 96 hours matin. In contrast to these subcellular changes, other after the removal of the culture medium shows that 59% { 2% of the cells undergo apoptosis. When cyclohexi-organelles remain relatively intact. In a very rapid promide, puromycin, or actinomycin D is added to the L37 cess lasting only minutes, the apoptotic cell fragments cultures, only cycloheximide is able to repress apoptosis, into membrane-encapsulated, smooth-surfaced apoindicating that the mechanism of apoptosis in the L37 ptotic bodies. The number and size of apoptotic bodies liver-derived cell line requires a cycloheximide-sensitive produced by a single ruptured cell vary. The apoptotic translational event. The extremely high rate of bodies may contain condensed nuclear or cytoplasmic apoptosis, together with the maintenance of hepatocel-material, including intact organelles. In vivo, the apo- 1601.)In our laboratory, we have developed a line of transgenic rats 13 in which the transgene is the mouse The loss of cell number homeostasis can occur either al...

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“…Both have been shown to inhibit DNA synthesis and induce apoptosis in primary hepatocyte cultures as well as in the liver of rats and mice in vivo (Oberhammer et al 1991, Oberhammer et al 1992, Schwall et al 1993, Hully et al 1994. However, so far it is unclear whether activin C or E have any similar potential.…”

Section: Discussionmentioning

confidence: 99%

Expression and dimerization of the rat activin subunits betaC and betaE: evidence for the ormation of novel activin dimers

Vejda¹,

Cranfield²,

Peter³

et al. 2002

Journal of Molecular Endocrinology

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Activins are cytokines of the transforming growth factor β family, which plays a central role in the determination of cell fate and the regulation of tissue balance. Family members are composed of two subunits and this dimerization is critical for liganding their cognate receptors and execution of proper functions. In the current study we focused on the localization of activin β A , β B , β C and β E subunits in the adult rat and analyzed the composition of putative activin β dimers. By dissecting tissue distribution of various activins, we found that the liver, in particular the hepatocytes, is the major source for activin β C and β E transcripts, since other tissues almost failed to express these isoforms. In sharp contrast, the emergence of activin β A and β B appeared ubiquitous. Using a highly selective proteome approach, we were able to identify homo-as well as heterodimers of individual activin subunits, indicating a high redundancy of ligand composition. Certainly, this broad potential to homo-and heterodimerize has to be considered in future studies on activin function.

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Activin induces cell death in hepatocytes in vivo and in vitro

Cited by 124 publications

References 23 publications

Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A

Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A

The Translational Inhibitor Cycloheximide Represses Growth Factor Depletion–Induced Apoptosis in An Alb–Sv40t Transgenic Rat Liver Cell Line

Expression and dimerization of the rat activin subunits betaC and betaE: evidence for the ormation of novel activin dimers

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