Expression of the Arf tumor suppressor gene is controlled by Tgfβ2 during development

Natalie E. Freeman-Anderson, Yanbin Zheng, Amy C. McCalla-Martin, Louise M. Treanor, Yi D. Zhao, Phillip M. Garfin, Tong Chuan He, Michelle N. Mary, J. Derek Thornton, Colleen Anderson, Melissa Gibbons, Raya Saab, Shannon H. Baumer, John M. Cunningham, Stephen X. Skapek

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18 Scopus citations

Abstract

The Arf tumor suppressor (also known as Cdkn2a) acts as an oncogene sensor induced by 'abnormal' mitogenic signals in incipient cancer cells. It also plays a crucial role in embryonic development: newborn mice lacking Arf are blind due to a pathological process resembling severe persistent hyperplastic primary vitreous (PHPV), a human eye disease. The cell-intrinsic mechanism implied in the oncogene sensor model seems unlikely to explain Arf regulation during embryo development. Instead, transforming growth factor β2 (Tgfβ2) might control Arf expression, as we show that mice lacking Tgfβ2 have primary vitreous hyperplasia similar to Arf-/- mice. Consistent with a potential linear pathway, Tgfβ2 induces Arf transcription and p19Arf expression in cultured mouse embryo fibroblasts (MEFs); and Tgfβ2-dependent cell cycle arrest in MEFs is maintained in an Arf-dependent manner. Using a new model in which Arf expression can be tracked by β-galactosidase activity in ArflacZ/+ mice, we show that Tgfβ2 is required for Arf transcription in the developing vitreous as well as in the cornea and the umbilical arteries, two previously unrecognized sites of Arf expression. Chemical and genetic strategies show that Arf promoter induction depends on Tgfβ receptor activation of Smad proteins; the induction correlates with Smad2 phosphorylation in MEFs and Arf-expressing cells in vivo. Chromatin immunoprecipitation shows that Smads bind to genomic DNA proximal to Arf exon 1β. In summary, Tgfβ2 and p19Arf act in a linear pathway during embryonic development. We present the first evidence that p19Arf expression can be coupled to extracellular cues in normal cells and suggest new mechanism for Arf control in tumor cells.

Original languageEnglish (US)
Pages (from-to)2081-2089
Number of pages9
JournalDevelopment
Volume136
Issue number12
DOIs
StatePublished - Jun 15 2009

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Keywords

  • Arf tumor suppressor gene
  • Mouse
  • Ocular development
  • Tgf beta

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology

Cite this

Freeman-Anderson, N. E., Zheng, Y., McCalla-Martin, A. C., Treanor, L. M., Zhao, Y. D., Garfin, P. M., He, T. C., Mary, M. N., Thornton, J. D., Anderson, C., Gibbons, M., Saab, R., Baumer, S. H., Cunningham, J. M., & Skapek, S. X. (2009). Expression of the Arf tumor suppressor gene is controlled by Tgfβ2 during development. Development, 136(12), 2081-2089. https://doi.org/10.1242/dev.033548