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First published online May 22, 2009
doi: 10.1242/10.1242/dev.033548

Development 136, 2081-2089 (2009)
Published by The Company of Biologists 2009
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Expression of the Arf tumor suppressor gene is controlled by Tgfβ2 during development

Natalie E. Freeman-Anderson1,*, Yanbin Zheng2,*, Amy C. McCalla-Martin1, Louise M. Treanor1, Yi D. Zhao2, Phillip M. Garfin2, Tong-Chuan He3, Michelle N. Mary1, J. Derek Thornton1, Colleen Anderson1, Melissa Gibbons2, Raya Saab4, Shannon H. Baumer2, John M. Cunningham2 and Stephen X. Skapek2,{dagger}

1 Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
2 Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA.
3 Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
4 Children's Cancer Center of Lebanon, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon.

{dagger} Author for correspondence (e-mail: sskapek{at}peds.bsd.uchicago.edu)

Accepted 14 April 2009

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 a new mechanism for Arf control in tumor cells.

Key words: Arf tumor suppressor gene, Ocular development, Tgf beta, Mouse


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