Activin A induces growth arrest through a SMAD- dependent pathway in hepatic progenitor cells

Abstract

BackgroundActivin A, an important member of transforming growth factor-β superfamily, is reported to inhibit proliferation of mature hepatocyte. However, the effect of activin A on growth of hepatic progenitor cells is not fully understood. To that end, we attempted to evaluate the potential role of activin A in the regulation of hepatic progenitor cell proliferation.ResultsUsing the 2-acetaminofluorene/partial hepatectomy model, activin A expression decreased immediately after partial hepatectomy and then increased from the 9th to 15th day post surgery, which is associated with the attenuation of oval cell proliferation. Activin A inhibited oval cell line LE6 growth via activating the SMAD signaling pathway, which manifested as the phosphorylation of SMAD2/3, the inhibition of Rb phosphorylation, the suppression of cyclinD1 and cyclinE, and the promotion of p21WAF1/Cip1 and p15INK4B expression. Treatment with activin A antagonist follistatin or blocking SMAD signaling could diminish the anti-proliferative effect of activin A. By contrast, inhibition of the MAPK pathway did not contribute to this effect. Antagonizing activin A activity by follistatin administration enhanced oval cell proliferation in the 2-acetylaminofluorene/partial hepatectomy model.ConclusionActivin A, acting through the SMAD pathway, negatively regulates the proliferation of hepatic progenitor cells.

Efficient endodermal induction of human adipose stem cells using various concentrations of Activin A for hepatic differentiation

“…SMAD2/3 is activated in cells upon exposure to Activin A and forms a complex with SMAD4 in the cytoplasm [22]. This complex is phosphorylated and moves into the nucleus [23].…”

Suberoylanilide hydroxamic acid enhances chemosensitivity to 5-fluorouracil in hepatocellular carcinoma via inhibition of thymidylate synthase

“…PCR was performed as described previously [35]. The primer sequences used were as follows: thymidylate synthase, sense 5′-TTTGGAGGAGTTGCTGTGGTT-3′ and antisense 5′-TTCTTCTGTCGTCAGGGTTGG-3′; and β-actin, sense 5′-TGCTATGTTGCCCTAGACTTCG-3′ and antisense 5′-GTTGGCATAGAGGTCTTTACGG-3′.…”

Esophageal squamous cell carcinoma invasion is inhibited by Activin A in ACVRIB-positive cells

“…A member of the TGFβ superfamily, Activin A, upon binding an Activin type II (ActRII/B) and type I (ACVRI/B) receptor, subsequently activates the Smad cascade thereby driving transcription of target genes (reviewed in [8]). Activin A was initially discovered as a gonadotroph, where it acts as a potent inducer of cell cycle arrest [9, 10]. In vivo knock-down of inhibin β A in mice leads to incomplete development [11] and defects in squamous tissue wound healing [12].…”