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:10.1002/hep.1840180219

Cited by 78 publications

(25 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, activin A can stimulate glycogenolysis (11) and inhibit DNA synthesis in isolated rat hepatocytes in vitro (12). In addition, infusion of activin A into rats caused hepatocellular necrosis around the central vein of the liver (13). These physiologic effects of activin on hepatocytes are consistent with findings that a major site of 125I-labeled activin A binding is the rat liver (14) and that the type II activin receptor is expressed in the mouse liver (ref.…”

supporting

confidence: 76%

“…At very early time points, inhibin-deficient mice develop liver pathology that mirrors the known effects of exogenous activins on the liver (13), suggesting that the elevated serum activins, secreted from the tumors, may be causing these aberrations. It is unclear whether the parietal cell depletion and mucosal atrophy are a direct result of the elevated activins or are secondary to the changes in the liver.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice.

Matzuk

Finegold

Mather

et al. 1994

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

343

266

View full text Add to dashboard Cite

Activins and inhibins, members of the tWe ( transforming growth factor superfamily of growth regulatory proteins, are produced in multiple tissues and affect diverse physiologic processes. Using embryonic stem cell technology, we previously demonstrated that inhibin can function as a gonadal tumor suppressor. In this study, we show that development of gonadal tumors is rapidly followed by a cancer cachexia-like wasting syndrome. Cachectic inhibin-deficient mice develop hepatocellular necrosis around the central vein and parietal cell depletion and mucosal atrophy in the glandular stomach, are anemic, and demonstrate severe weight loss. The liver pathology is consistent with studies demonstrating an effect of elevated activins on rat hepatocytes. In inhibindeficient mice with tumors, activins are >10-fold elevated in the serum and are likely causing some of the cachexia symptoms. In contrast, inhibin-deficient mice gonadectomized at an early age do not develop this wasting syndrome. However, these gonadectomized, inhibin-deficient mice eventually develop adrenal cortical sex steroidogenic tumors with nearly 100% penetrance, demonstrating that inhibin is also a tumor suppressor for the adrenal gland.The inhibins (a:(3 heterodimers) and activins (13:l3dimers) are related proteins that share common 13 subunits (either 13A or PB subunits) (1). These proteins, members of a large family of structurally related growth regulatory proteins, which includes the type (3 transforming growth factors (TGF-P), bone morphogenetic proteins, and Mullerian inhibiting substance (MIS) (1-4), have been shown to have diverse functions in a variety of assay systems including antiproliferative effects on carcinoma cell lines [i.e., MIS and TGF-p (2, 3)].The activins and inhibins also have diverse functions in mammalian physiology and development. Activin and inhibin subunit mRNAs and proteins are synthesized in a variety of cell types and embryonic and adult tissues in different species (1,(5)(6)(7)(8)(9)(10). In the adult mammal, although activins were initially discovered for their ability to stimulate pituitary follicle-stimulating hormone secretion, they have also been shown to influence other functions including liver metabolism and glucose regulation. For example, activin A can stimulate glycogenolysis (11) and inhibit DNA synthesis in isolated rat hepatocytes in vitro (12). In addition, infusion of activin A into rats caused hepatocellular necrosis around the central vein of the liver (13). These physiologic effects of activin on hepatocytes are consistent with findings that a major site of 125I-labeled activin A binding is the rat liver (14) and that the type II activin receptor is expressed in the mouse liver (ref. 15; R. Towns and M.M.M., unpublished data).Using embryonic stem cell technology, we have generated inhibin-deficient mice (16), which develop sex cord stromal tumors at an early age with nearly 1001% penetrance, demonstrating that inhibin functions in vivo as a tumor suppressor in the gonads of mice (16). In th...

show abstract

supporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice.

Matzuk

Finegold

Mather

et al. 1994

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

343

266

View full text Add to dashboard Cite

show abstract

“…These structurally related but functionally diverse polypeptides control the growth and differentiation of many cell types (3)(4)(5). In addition, activins regulate the production of follicle-stimulating hormone and other hormones by the anterior pituitary (6 -8) and have diverse endocrine, paracrine, and autocrine actions throughout the reproductive (9), immune (10,11), hematopoietic (12,13), endocrine (7), and central nervous systems (14). Activins also play key roles in numerous pathophysiologic processes including carcinogenesis (15).…”

mentioning

confidence: 99%

Identification of a Functional Binding Site for Activin on the Type I Receptor ALK4

Harrison¹,

Gray²,

Koerber

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Activins, like other members of the transforming growth factor-␤ (TGF-␤) superfamily, initiate signaling by assembling a complex of two types of transmembrane serine/threonine receptor kinases classified as type II (ActRII or ActRIIB) and type I (ALK4). A kinase-deleted version of ALK4 can form an inactive complex with activin and ActRII/IIB and thereby acts in a dominant negative manner to block activin signaling. Using the complex structure of bone morphogenetic protein-2 bound to its type I receptor (ALK3) as a guide, we introduced extracellular domain mutations in the context of the truncated ALK4 (ALK4-trunc) construct and assessed the ability of the mutants to inhibit activin function. We have identified five hydrophobic amino acid residues on the ALK4 extracellular domain (Leu 40 , Ile 70 , Val 73 , Leu 75 , and Pro 77 ) that, when mutated to alanine, have substantial effects on ALK4-trunc dominant negative activity. In addition, eleven mutants partially affected activin binding to ALK4. Together, these residues likely constitute the binding surface for activin on ALK4. Cross-linking studies measuring binding of 125 Iactivin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. Our results indicate that there is only a partial overlap of the binding sites on ALK4 and ALK3 for activin-A and bone morphogenetic protein-2, respectively. In addition three of the residues required for activin binding to ALK4 are conserved on the type I TGF-␤ receptor ALK5, suggesting the corresponding region on ALK5 may be important for TGF-␤ binding.Activins are members of the transforming growth factor-␤ (TGF-␤) 1 superfamily, which also includes the TGF-␤ (1) and bone morphogenetic protein (BMP) (2) families. These structurally related but functionally diverse polypeptides control the growth and differentiation of many cell types (3-5). In addition, activins regulate the production of follicle-stimulating hormone and other hormones by the anterior pituitary (6 -8) and have diverse endocrine, paracrine, and autocrine actions throughout the reproductive (9), immune (10, 11), hematopoietic (12, 13), endocrine (7), and central nervous systems (14). Activins also play key roles in numerous pathophysiologic processes including carcinogenesis (15). Activins (ϳ26 kDa) are disulfide-linked dimers of related polypeptides consisting of two ␤ chains (activin-A (␤A-␤A), activin-AB (␤A-␤B), and activin-B (␤B-␤B)) (16). The structure of these factors is determined by several conserved cysteine residues that form disulfide bonds in the tightly folded cystine-knot motif that is shared by TGF-␤ superfamily members (17).The signaling events initiated by activin require binding of two types of transmembrane serine/threonine receptor kinases classified as type II (ActRII or ActRIIB) and type I (ALK4). Both receptors are transmembrane proteins with ligand binding activity in the extracellular domain and serine/threonine kinase activity in the intracellular domain (15). The activin type II receptors are the primary li...

show abstract

“…12,13) Recent studies have shown that activin A plays several roles in rat liver in vivo and in vitro. [13][14][15][16][17] It inhibits mitogeninduced DNA synthesis in vitro, 14) induces hepatocellular apoptosis in vivo and vitro, [15][16][17] and stimulates glycogenolysis in vitro.…”

mentioning

confidence: 99%

Effect of Activins AB and B on DNA Synthesis Stimulated by Epidermal Growth Factor in Primary Cultured Rat Hepatocytes.

Niimi¹,

Horikawa

Seki

et al. 2002

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Activins are members of the transforming growth factor-b superfamily and are homodimeric proteins composed of two inhibin/activin b-subunits linked by a disulfide bridge. Activin was originally identified as a stimulator of FSH (follicle-stimulating hormone) secretion. [6][7][8] Later, activins were shown to be expressed in various organs during development and in acquired conditions, and to have a wide variety of biological functions, including regulation of cell proliferation and differentiation, and induction of mesodermal tissues during amphibian development. 12,13) Recent studies have shown that activin A plays several roles in rat liver in vivo and in vitro. [13][14][15][16][17] It inhibits mitogeninduced DNA synthesis in vitro, 14) induces hepatocellular apoptosis in vivo and vitro, [15][16][17] and stimulates glycogenolysis in vitro.18) Activin C has been reported to have no effect on DNA synthesis by liver tumor cell line HepG2.11) However, there have been no reports on the actions of activin AB and B in rat liver either in vivo or in vitro. It, therefore, seemed meaningful to examine the effect of activins AB and B on the liver functions that have been shown to be regulated by activin A. In this regard, we were especially interested in mitogen-stimulated DNA synthesis as a model system for its biological significance, because expression of b A and b B mRNA in rat liver has been found to change markedly in rat models of liver regeneration. 14,19) In this paper, we examined the effect of activins AB and B on DNA synthesis stimulated by epidermal growth factor (EGF) in primary cultured rat hepatocytes and compared their effect with that of activin A. MATERIALS AND METHODS MaterialsThe materials used for cell isolation and cell culture were the same as reported by Tanaka et al. 20) Recombinant human (rh) activin A was kindly provided by Dr. Y. Eto (Ajinomoto Co., Inc., Japan). Porcine activin A, activin AB, and activin B were purchased from Wako (Osaka, Japan). EGF was obtained from Toyobo (Osaka). [3 H]thymidine (89.9 Ci/mmol) was purchased from NEN Life Science Products (Boston, MA, U.S.A.).Cell Isolation and Monolayer Culture Parenchymal hepatocytes were isolated from adult male Wistar strain rats weighing 180-200 g by in situ perfusion of the liver with collagenase, 20) and they were suspended, 2ϫ10 5 cells/ml, in Williams' E medium containing 5% fetal bovine serum, 10 nM insulin, and 1 nM dexamethasone, and cultured at 0.2ϫ10 5 cells/cm 2 in a 48-well and 6-well microplate (IWAKI) precoated with collagen type-1 AC in a humidified chamber at 37°C under 5% CO 2 and 30% O 2 in air. Cells plated in the 48-well and 6-well plate were used to measure DNA synthesis and [ 125 I]rh activin A binding, respectively. After 2.5 h, the medium was replaced with serum-and hormone-free medium containing aprotinin (1 mg/ml). Measurement of [ 3 H]thymidine IncorporationAfter 15 h, the medium was replaced with hormone-free medium containing aprotinin (1 mg/ml) and 0.1% bovine serum albumin (BSA), and various hormones we...

show abstract

Activin induces cell death in hepatocytes in vivo and in vitro

Cited by 78 publications

References 23 publications

Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice.

Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice.

Identification of a Functional Binding Site for Activin on the Type I Receptor ALK4

Effect of Activins AB and B on DNA Synthesis Stimulated by Epidermal Growth Factor in Primary Cultured Rat Hepatocytes.

Contact Info

Product

Resources

About