p19Arf represses platelet-derived growth factor receptor β by transcriptional and posttranscriptional mechanisms

Ryan C. Widau, Yanbin Zheng, Caroline Y. Sung, Anna Zelivianskaia, Lauren E. Roach, Karen M. Bachmeyer, Tatiana Abramova, Aurelie Desgardin, Andrew Rosner, John M. Cunningham, Stephen X. Skapek

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12 Scopus citations

Abstract

In addition to cancer surveillance, p19Arf plays an essential role in blocking signals stemming from platelet-derived growth factor receptor β (Pdgfrβ) during eye development, but the underlying mechanisms have not been clear. We now show that without Arf, pericyte hyperplasia in the eye results from enhanced Pdgfrβ-dependent proliferation from embryonic day 13.5 (E13.5) of mouse development. Loss of Arf in the eye increases Pdgfrβ expression. In cultured fibroblasts and pericyte-like cells, ectopic p19Arf represses and Arf knockdown enhances the expression of Pdgfrβ mRNA and protein. Ectopic Arf also represses primary Pdgfrβ transcripts and a plasmid driven by a minimal promoter, including one missing the CCAAT element required for highlevel expression. p19Arf uses both p53-dependent and -independent mechanisms to control Pdgfrβ. In vivo, without p53, Pdgfrβ mRNA is elevated and eye development abnormalities resemble the Arf-/- phenotype. However, effects of p53 on Pdgfrβ mRNA do not appear to be due to direct p53 or RNA polymerase II recruitment to the promoter. Although p19Arf controls Pdgfrβ mRNA in a p53-dependent manner, it also blunts Pdgfrβ protein expression by blocking new protein synthesis in the absence of p53. Thus, our findings demonstrate a novel capacity for p19Arf to control Pdgfrβ expression by p53-dependent and -independent mechanisms involving RNA transcription and protein synthesis, respectively, to promote the vascular remodeling needed for normal vision.

Original languageEnglish (US)
Pages (from-to)4270-4282
Number of pages13
JournalMolecular and Cellular Biology
Volume32
Issue number21
DOIs
StatePublished - Nov 2012

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Widau, R. C., Zheng, Y., Sung, C. Y., Zelivianskaia, A., Roach, L. E., Bachmeyer, K. M., Abramova, T., Desgardin, A., Rosner, A., Cunningham, J. M., & Skapek, S. X. (2012). p19Arf represses platelet-derived growth factor receptor β by transcriptional and posttranscriptional mechanisms. Molecular and Cellular Biology, 32(21), 4270-4282. https://doi.org/10.1128/MCB.06424-11