p19Arf represses platelet-derived growth factor receptor β by transcriptional and posttranscriptional mechanisms.
In addition to cancer surveillance, p19(Arf) 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 p19(Arf) 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 high-level expression. p19(Arf) 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 p19(Arf) 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 p19(Arf) 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.
Department of Pediatrics, Section of Hematology/Oncology and Stem Cell Transplantation, University of Chicago, Chicago, Illinois, USA.
Ryan C
RC
Widau
Yanbin
Y
Zheng
Caroline Y
CY
Sung
Anna
A
Zelivianskaia
Lauren E
LE
Roach
Karen M
KM
Bachmeyer
Tatiana
T
Abramova
Aurelie
A
Desgardin
Andrew
A
Rosner
John M
JM
Cunningham
Stephen X
SX
Skapek
D020727:ADP-Ribosylation Factors / Q000235:genetics; D000818:Animals; D002460:Cell Line; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005123:Eye / Q000098:blood supply / Q000196:embryology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020286:Pericytes / Q000166:cytology / Q000502:physiology; D014176:Protein Biosynthesis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008565:Membrane Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D020797:Receptor, Platelet-Derived Growth Factor beta; D012319:RNA Polymerase II; C097313:ADP-ribosylation factor related proteins; D020727:ADP-Ribosylation Factors