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Tumor Suppressors p53 and TGFβ Converge to Regulate the Alpha-Fetoprotein Oncodevelopmental Tumor Marker

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Transforming Growth Factor-β in Cancer Therapy, Volume II

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Numerous clues, collected from a diverse array of studies, hinted at an intersection between p53 and TGFβ signaling in the regulation of growth arrest and tumor suppression. Now, conclusive evidence linking the two major tumor suppressor paths has been provided by multiple, independent approaches. Here, we discuss the biochemical and molecular characterization that led to the identification of p53 and TGFβ effectors, Smad and SnoN proteins, as cooperative regulators of AFP expression. Interaction of these transcription factors at a composite regulatory element of overlapping p53 and Smad binding sequences evicts the Foxa1 transactivator protein, targets histone modifiers, and alters chromatin structure. These changes in chromatin effect AFP repression during development of liver tissue and in hepatoma cells, which overexpress AFP as a tumor marker, in response to TGFβ. Our analyses of RNA-interference (RNAi)-depleted hepatoma cells and p53-null mice show that p53 and TGFβ signaling act cooperatively and that p73 partially compensates for loss of p53. We also summarize, in this chapter, studies that revealed a required intersection between p53 and TGFβ signaling in activating genes essential for Xenopus embryogenesis, as well as cell cycle arrest of tumor-derived cells. Clearly, regulation of a specific subset of genes requires both p53 and TGFβ signaling, a process likely dictated by tissue-specific expression of coactivators and repressors and modified by numerous signaling inputs. Understanding this cooperative regulatory network may offer new insights into restoration of normal cellular differentiation and tumor suppression.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Graduate School of Biological Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Deepti S. Wilkinson PhD & Michelle Craig Barton PhD

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  1. Deepti S. Wilkinson PhD
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  2. Michelle Craig Barton PhD
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Editors and Affiliations

  1. Cancer Training Branch, Office of Centers, Training and Resources, National Cancer Institute, Bethesda, MD

    Sonia B. Jakowlew PhD

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Wilkinson, D.S., Barton, M.C. (2008). Tumor Suppressors p53 and TGFβ Converge to Regulate the Alpha-Fetoprotein Oncodevelopmental Tumor Marker. In: Jakowlew, S.B. (eds) Transforming Growth Factor-β in Cancer Therapy, Volume II. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-293-9_20

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  • DOI: https://doi.org/10.1007/978-1-59745-293-9_20

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-715-0

  • Online ISBN: 978-1-59745-293-9

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