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PNAS 105 (21): 7612-7617

Copyright © 2008 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / PHYSIOLOGY

Synergistic upregulation of erythropoietin receptor (EPO-R) expression by sense and antisense EPO-R transcripts in the canine lung

Quiyang Zhang*, Jianning Zhang*, Orson W. Moe*,{dagger},{ddagger}, and Connie C. W. Hsia*,§

Departments of *Internal Medicine and {dagger}Physiology, {ddagger}Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034

Communicated by Ewald R. Weibel, University of Bern, Bern, Switzerland, March 14, 2008

Received for publication September 25, 2007.

Abstract: We previously found increased erythropoietin receptor (EPO-R) protein levels in vigorously growing canine lungs after pneumonectomy (PNX), suggesting a role for paracrine EPO signaling in lung growth and remodeling. Now we find that sense and antisense EPO-R transcripts (sEPO-R and asEPO-R, respectively) are concordantly up-regulated in the post-PNX remaining lung, leading to the hypothesis that sEPO-R and asEPO-R interactions enhance EPO signaling during lung growth. We cloned a canine asEPO-R cDNA, which is fully complementary to the sense strand of the EPO-R gene from 2.5kb 3' to the sense stop codon, and extends into the 5' UTR of the sEPO-R transcript. Both asEPO-R and sEPO-R transcripts colocalize with EPO-R protein in the same lung cells. In cultured human embryonic kidney (HEK293) cells, transfection with sEPO-R (+FLAG tag) cDNA alone increased EPO-R protein expression (anti-EPO-R and anti-FLAG). At constant sEPO-R cDNA levels, cotransfection with escalating asEPO-R cDNA further increased recombinant EPO-R protein expression. The asEPO-R transcript harbors two putative opening reading frames (ORFs). Separate transfection of each asEPO-R ORF cDNA resulted in differential stimulatory effects on EPO-R protein expression. We conclude that both sEPO-R and asEPO-R transcripts contribute to in vivo up-regulation of EPO-R protein expression in the post-PNX remaining lung. This demonstrates synergism between sense–antisense EPO-R transcripts in response to physiological stimulation in a robust model of induced lung growth.

Key Words: compensatory lung growth • pneumonectomy


Author contributions: Q.Z., O.W.M., and C.C.W.H. designed research; Q.Z., J.Z., O.W.M., and C.C.W.H. performed research; Q.Z., J.Z., O.W.M., and C.C.W.H. analyzed data; and Q.Z., O.W.M., and C.C.W.H. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0802467105/DCSupplemental.

§To whom correspondence should be addressed. E-mail: connie.hsia{at}utsouthwestern.edu

© 2008 by The National Academy of Sciences of the USA


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