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Trenton Place


trenton-place@uiowa.edu
Mentor: Frederick Domann, Ph.D.
Lab Room: 4219 MERF
Lab Phone: 319-335-8024

Epigenetic silencing of PHD3 in a diverse array of human cancers

The HIF prolyl-hydroxylases (PHD1, 2 and 3) play an important role in the cellular response to hypoxia by regulating HIF-α protein levels. Normally, PHD3 is significantly upregulated in cells following hypoxic exposure, and acts to control HIF-α expression under hypoxic conditions. This is important because loss of control of HIF-α protein expression is known to promote malignancies such as renal cell carcinoma and pheochromocytoma. Previous studies utilizing human cancer cell lines from diverse tissues of origin have demonstrated that PHD3 expression is silenced in a significant number of these cells, and is not able to be upregulated following exposure to hypoxia. We have determined that DNA methylation of the PHD3 promoter is at least part of the mechanism by which these cell lines fail to express PHD3 basally, and fail to upregulate PHD3 expression in response hypoxia. Interestingly though, we were unable to demonstrate that HIF-1α protein levels were differentially affected in PHD3 silenced vs. PHD3 expressing human cancer cell lines. This suggests that human tumor cells may silence PHD3 for reasons other than to stabilize HIF-1α protein expression. Therefore, we are currently investigating other tumor-survival pathways that may be affected by PHD3 silencing.

Publications:

Place TL, Fitzgerald MP, Venkataraman S, Vorrink SU, Case AJ, Teoh ML, Domann FE. Aberrant promoter CpG methylation is a mechanism for impaired PHD3 expression in a diverse set of malignant cells. PLoS One. 2011 Jan 28;6(1):e14617. PubMed PMID: 21297970; PubMed Central PMCID: PMC3030558.

Visser Smit GD, Place TL, Cole SL, Clausen KA, Vemuganti S, Zhang G, Koland JG, Lill NL. Cbl controls EGFR fate by regulating early endosome fusion. Sci Signal. 2009 Dec 22;2(102):ra86. PubMed PMID: 20029031; PubMed Central PMCID:PMC2813709.

Cao XR, Lill NL, Boase N, Shi PP, Croucher DR, Shan H, Qu J, Sweezer EM, Place T, Kirby PA, Daly RJ, Kumar S, Yang B. Nedd4 controls animal growth by regulating IGF-1 signaling. Sci Signal. 2008 Sep 23;1(38):ra5. PubMed PMID: 18812566; PubMed Central PMCID: PMC2833362.

Stern KA, Place TL, Lill NL. EGF and amphiregulin differentially regulate Cbl recruitment to endosomes and EGF receptor fate. Biochem J. 2008 Mar 15;410(3):585-94. PubMed PMID: 18045238.

Stern KA, Visser Smit GD, Place TL, Winistorfer S, Piper RC, Lill NL. Epidermal growth factor receptor fate is controlled by Hrs tyrosine phosphorylation sites that regulate Hrs degradation. Mol Cell Biol. 2007 Feb;27(3):888-98. Epub 2006 Nov 13. PubMed PMID: 17101784; PubMed Central PMCID: PMC1800687.

Selected Abstracts:

Place TL, Fitzgerald MP, Venkataraman S, Vorrink SU, Case AJ, et al. 2011 Aberrant Promoter CpG Methylation Is a Mechanism for Impaired PHD3 Expression in a Diverse Set of Malignant Cells. Society for Free Radical Biology and Medicine 2010 annual meeting.

Place T, Hohl, RJ. Effects of Erythropoietin on Cancer Cell VEGF Produceion. Doris Duke Clinical Research Fellowship Program Annual Meeting. University of North Carolina, NC. May 2009.

Place T, Schmitz D, Pitstick L, Campione A, Winkle LV. Glutamate and C-myc: Interplay for the Growth and Maintenance of Pluirpotent Human Embryonic Stem Cells? Midwestern University Research Day, Poster Presentation, Midwestern University, May 2008.

Place T, Stern K, Lill N. Mapping the Site of Hrs Regulation by Cbl. University of Iowa Biosciences Undergraduate Poster Competition, Poster Presentation, University of Iowa, September 2004.

Place T, Stern K, Lill N. Mapping the Site of Hrs. Regulation by Cbl. American Society for Biochemistry and Molecular Biology, Poster Presentation, Boston, MA, June 2004.

Honors and Awards

  • Graduate Student Senate Travel Award, 2010, University of Iowa
  • Young Investigator Award, 2010 Society for Free Radical Biology and Medicine
  • Doris Duke Clinical Research Fellow, 2008-2009
  • Midwestern University Basic Science award in Biochemistry (Class of 2010)
  • Summer Medical Student Research Fellowship (Midwestern University)
  • Poster Prize, University of Iowa Biosciences Undergraduate Poster Competition
  • 2003 Summer Undergraduate Research Fellowship, University of Iowa Department of Pharmacology
  • Travel Award, American Society of Biochemistry and Molecular Biology (ASBMB). June 2004
  • Summer Medical Student Research Fellowship (Midwestern University/CCOM). 2007
  • Institute for Clinical and Translational Medicine TL-1 Linked Training Award November 2011
  • American Medical Association Foundation Seed Grant, March 2012
  • Student Osteopathic Medical Association Student Research Fellowship, April 2012
  • American Osteopathic Medical Association Research Conference Poster Award, October 2012