Journal Article

Transforming growth factor-β1-induced Smad signaling, cell-cycle arrest and apoptosis in hepatoma cells

Christoph Lars Buenemann, Claudia Willy, Albrecht Buchmann, Alexander Schmiechen and Michael Schwarz

in Carcinogenesis

Volume 22, issue 3, pages 447-452
Published in print March 2001 | ISSN: 0143-3334
Published online March 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.3.447
Transforming growth factor-β1-induced Smad signaling, cell-cycle arrest and apoptosis in hepatoma cells

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Transforming growth factor-β1 (TGFβ) is involved in the regulation of liver cell proliferation and apoptosis, and escape of hepatoma cells from the growth restraining signals of TGFβ has been suggested to contribute to tumor development. TGFβ modulates gene transcription by receptor-mediated activation of Smad proteins which act as transcription factors. TGFβ-mediated primary signaling responses as well as effects on the cell cycle and apoptosis were investigated in the human hepatoblastoma line HepG2, the rat hepatoma line FTO-2B and the mouse hepatoma line 55.1c. Activation of a Smad (Sma and Mad homolog) response-element-driven luciferase reporter by TGFβ was very similar in all three cell lines, indicating functionality of the primary TGFβ signaling pathway. Moreover, TGFβ-inducible early gene was transiently activated by TGFβ in all cell lines as shown by RT–PCR. HepG2 cells, however, were completely resistant to TGFβ-induced growth arrest and apoptosis and 55.1c cells were only slightly susceptible to TGFβ-induced apoptosis. By contrast, treatment of FTO-2B cells with TGFβ led to a partial G0/G1 arrest and a strong induction of apoptosis. TGFβ-induced apoptosis of FTO-2B cells was inhibited by dexamethasone, insulin, phenobarbital and dieldrin. Of these agents, only insulin led to a significant reduction of TGFβ-stimulated Smad-reporter activity, suggesting that the other compounds interfere with TGFβ-induced apoptosis downstream of Smad-mediated primary transcriptional responses at a level that may be constitutively altered in apoptosis-resistant hepatoma cell lines.

Keywords: Cdk, cyclin-dependent kinase; EGRα, early growth response α; Erk1/2, extracellular signal-regulated kinases 1/2; M6P/IGF2, mannose-6-phosphate/insulin-like growth factor-II; PBS, phosphate buffered saline; RT–PCR, reverse transcription–polymerase chain reaction; SBE, Smad binding element; Smad, Sma and Mad homolog; TGFβ, transforming growth factor-β1; TIEG, TGFβ-inducible early gene.

Journal Article.  5016 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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