Expression of theArftumor suppressor gene is controlled by Tgfβ2 during development

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. Arf expression can be coupled to extracellular cues in normal cells and suggest a new mechanism for Arf control in tumor cells.

Tgfβ Signaling Directly Induces Arf Promoter Remodeling by a Mechanism Involving Smads 2/3 and p38 MAPK

“…Supporting the importance of this finding, mouse embryos lacking Tgf␤2 have primary vitreous hyperplasia similar to that observed in Arf Ϫ/Ϫ embryos (14,15). Importantly, these observations can be replicated in vitro because exogenous Tgf␤2 enhances Arf expression in cultured MEFs and maintains a proliferation arrest in an Arf-dependent manner (13), thereby providing a model system to further investigate mechanisms.…”

“…In some experiments, early passage wild type MEFs were infected with retrovirus encoding H-RAS V12 and treated with SB203580 (20 M) and SB431542 (10 M) concurrently. For all studies Western blotting and ␤-galactosidase assays were performed in wild type and Arf lacZ/lacZ MEFs, respectively, as previously described (13). Experimental findings were confirmed in at least two independent experiments, with quantitative data from ␤-galactosidase assays pooled from all representative experiments.…”

“…Using a candidate-gene approach, transforming growth factor ␤2 (Tgf␤2), a member of the Tgf␤ cytokine superfamily, was recently found to be critical for Arf expression at several sites in the developing mouse (13). Supporting the importance of this finding, mouse embryos lacking Tgf␤2 have primary vitreous hyperplasia similar to that observed in Arf Ϫ/Ϫ embryos (14,15).…”

“…fl/ϩ (17), Arf Gfp/ϩ (18), and Arf lacZ/ϩ (13) mice were maintained in a mixed C57BL/6 ϫ 129/Sv genetic background. Tgf␤2 ϩ/Ϫ mice (14) were purchased from The Jackson Laboratory (Bar Harbor, ME).…”

Lack of Fetuin-A (α2-HS-Glycoprotein) Reduces Mammary Tumor Incidence and Prolongs Tumor Latency via the Transforming Growth Factor-β Signaling Pathway in a Mouse Model of Breast Cancer

“…38 Experiments also suggest that p53 activation conveys cues from extracellular signals within the TGF-␤ gene expression program and support the idea that p53 acts as an integration node between Ras/mitogen-activated protein kinase and TGF-␤ pathways. 27 The strong in vivo TGF-␤ signaling in the absence of fetuin-A most likely induces the p19(Arf) transcription in the mammary tissues, 39 resulting in the up-regulation of p53. The up-regulated p53 in the absence of fetuin-A, in turn, would amplify TGF-␤ signaling.…”