Expression of the Arf tumor suppressor gene is controlled by Tgfbeta2 during development. Development 2009 Jun;136(12):2081-9
Date
05/26/2009Pubmed ID
19465598Pubmed Central ID
PMC2685726DOI
10.1242/dev.033548Scopus ID
2-s2.0-69549101925 (requires institutional sign-in at Scopus site) 27 CitationsAbstract
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 beta2 (Tgfbeta2) might control Arf expression, as we show that mice lacking Tgfbeta2 have primary vitreous hyperplasia similar to Arf(-/-) mice. Consistent with a potential linear pathway, Tgfbeta2 induces Arf transcription and p19(Arf) expression in cultured mouse embryo fibroblasts (MEFs); and Tgfbeta2-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 beta-galactosidase activity in Arf(lacZ/+) mice, we show that Tgfbeta2 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 Tgfbeta 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 1beta. In summary, Tgfbeta2 and p19(Arf) act in a linear pathway during embryonic development. We present the first evidence that p19(Arf) expression can be coupled to extracellular cues in normal cells and suggest a new mechanism for Arf control in tumor cells.
Author List
Freeman-Anderson NE, Zheng Y, McCalla-Martin AC, Treanor LM, Zhao YD, Garfin PM, He TC, Mary MN, Thornton JD, Anderson C, Gibbons M, Saab R, Baumer SH, Cunningham JM, Skapek SXAuthor
Shannon H. Baumer-Mouradian MD Assistant Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCells, Cultured
Cyclin-Dependent Kinase Inhibitor p16
Embryo, Mammalian
Eye Abnormalities
Fibroblasts
Mice
Mice, Transgenic
Phosphorylation
Signal Transduction
Transcriptional Activation
Transforming Growth Factor beta2
