Journal Article

Interactions between MYC and transforming growth factor alpha alter the growth and tumorigenicity of liver progenitor cells

Ronald S.Y. Cheung, John T. Brooling, Melissa M. Johnson, Kimberly J. Riehle, Jean S. Campbell and Nelson Fausto

in Carcinogenesis

Volume 28, issue 12, pages 2624-2631
Published in print December 2007 | ISSN: 0143-3334
Published online August 2007 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm184
Interactions between MYC and transforming growth factor alpha alter the growth and tumorigenicity of liver progenitor cells

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The MYC oncogene induces both cell proliferation and apoptosis. The apoptotic function of MYC is thought to inhibit carcinogenesis; thus, when disrupted, tumorigenic potential is increased. Both MYC and transforming growth factor alpha (TGFα) are commonly over-expressed in hepatocellular carcinomas, and transgenic mice expressing these genes rapidly develop tumors via the suppression of MYC-induced apoptosis by the growth factor. However, the nature of the interactions between MYC and TGFα are not well understood. Specifically, it is unclear whether TGFα acts only as an anti-apoptotic factor in its interactions with MYC or whether it has substantial effects on cell growth. We investigated whether TGFα can provide additional mitogenic signals if it is not required to act as an anti-apoptotic factor. We demonstrate that expression of MYC and TGFα in liver progenitor cells (known as oval cells) results in enhanced cell proliferation in culture and the generation of poorly differentiated tumors after inoculation into nude mice. We further demonstrate that while the apoptosis-deficient T58A and S71F alleles of MYC retain their ability to promote oval cell proliferation, they have opposite growth interactions with TGFα. The T58A allele has a stimulatory effect on both proliferation and tumorigenicity. In contrast, co-expression of the S71F allele reduces proliferation and slows tumor development. We conclude that the tumorigenic growth effects of MYC in TGFα-expressing liver progenitor cells are not solely dependent on its apoptotic activity.

Journal Article.  5690 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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