Photo of Mary R. Loeken,  PhD

Mary R. Loeken, PhD

Joslin Diabetes Center

Joslin Diabetes Center
Phone: (617) 309-2525
Fax: (617) 309-2650


mary.loeken@joslin.harvard.edu

Mary R. Loeken, PhD

Joslin Diabetes Center

EDUCATIONAL TITLES

  • Associate Professor, Medicine, Harvard Medical School
  • Investigator, Section on Islet and Regenerative Cell Biology, Joslin Diabetes Center

DF/HCC PROGRAM AFFILIATION

Research Abstract

We are interested in the role of the Pax-3 transcription factor in neuroepithelial/neural crest development. This research initiated in an effort to understand the causes of neural tube and cardiac neural crest defects in the offspring of mothers with diabetes. Using a mouse model of diabetic pregnancy, we found that expression of Pax-3 is significantly impaired, and consequently, Pax-3-deficient cells undergo apoptosis. We recently found that Pax-3 down regulates p53 protein (by stimulating Mdm2-mediated ubiquitination), thereby suppressing p53-dependent apoptosis. While suppression of p53-dependent apoptosis by Pax-3 may be a necessary process during neuroepithelial/neural crest development, this could contribute to the oncogenic process in tumors derived from PAX-3-expressing tissues (such as neuroblastoma, Ewing's sarcoma, melanoma, and pediatric rhabdomyosarcoma), in which PAX-3 re-emerges. We have two areas of research related to the mission of DF/HCC: (a) to investigate the role of Pax-3 suppression of p53-dependent cell cycle withdrawal or apoptosis on neuroepithelial and neural crest cell fate; (b) to study new embryonic cell lines derived from embryos carrying wild type or mutant Pax-3 alleles in various combination with wild type or mutant p53 alleles with which to study regulation of metabolism in embryonic cells, effects on Pax3 expression, and effects of Pax3 on p53 stability, proliferation, and differentiation.

Publications

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  • Wei D, Loeken MR. Increased DNA Methyltransferase 3b (Dnmt3b) -mediated CpG Island Methylation Stimulated by Oxidative Stress Inhibits Expression of a Gene Required for Neural Tube and Neural Crest Development in Diabetic Pregnancy. Diabetes 2014. PubMed
  • Loeken MR. Intersection of complex genetic traits affecting maternal metabolism, fetal metabolism, and neural tube defect risk: Looking for needles in multiple haystacks. Mol Genet Metab 2014; 111:415-7. PubMed
  • Jung JH, Wang XD, Loeken MR. Mouse embryonic stem cells established in physiological-glucose media express the high KM Glut2 glucose transporter expressed by normal embryos. Stem Cells Transl Med 2013; 2:929-34. PubMed
  • Wu Y, Viana M, Thirumangalathu S, Loeken MR. AMP-activated protein kinase mediates effects of oxidative stress on embryo gene expression in a mouse model of diabetic embryopathy. Diabetologia 2011. PubMed
  • Wang XD, Morgan SC, Loeken MR. Pax3 Stimulates p53 Ubiquitination and Degradation Independent of Transcription. PLoS ONE 2012; 6:e29379. PubMed
  • Zabihi S, Loeken MR. Understanding diabetic teratogenesis: Where are we now and where are we going? Birth Defects Res A Clin Mol Teratol 2010; 88:779-90. PubMed
  • Loeken MR. How TGF-beta and PAX3 regulate suntanning. Pigment Cell Melanoma Res 2009; 22:146-7. PubMed
  • Chappell JH Jr,Wang XD,Loeken MR. Diabetes and apoptosis: neural crest cells and neural tube. Apoptosis 2009. PubMed
  • Loeken MR. Challenges in understanding diabetic embryopathy. Diabetes 2008; 57:3187-8. PubMed
  • Morgan SC, Relaix F, Sandell LL, Loeken MR. Oxidative stress during diabetic pregnancy disrupts cardiac neural crest migration and causes outflow tract defects. Birth Defects Res A Clin Mol Teratol 2008; 82:453-63. PubMed
  • Li R, Thorens B, Loeken MR. Expression of the gene encoding the high-K (m) glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy. Diabetologia 2007; 50:682-9. PubMed
  • Wang F, Thirumangalathu S, Loeken MR. Establishment of new mouse embryonic stem cell lines is improved by physiological glucose and oxygen. Cloning Stem Cells 2006; 8:108-16. PubMed
  • King GL, Loeken MR. Hyperglycemia-induced oxidative stress in diabetic complications. Histochem Cell Biol 2004; 122:333-8. PubMed
  • Loeken MR. Free radicals and birth defects. J Matern Fetal Neonatal Med 2004; 15:6-14. PubMed
  • Chang TI, Horal M, Jain SK, Wang F, Patel R, Loeken MR. Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects. Diabetologia 2003; 46:538-45. PubMed
  • Pani L, Horal M, Loeken MR. Polymorphic susceptibility to the molecular causes of neural tube defects during diabetic embryopathy. Diabetes 2002; 51:2871-4. PubMed
  • Chan BW, Chan KS, Koide T, Yeung SM, Leung MB, Copp AJ, Loeken MR, Shiroishi T, Shum AS. Maternal diabetes increases the risk of caudal regression caused by retinoic acid. Diabetes 2002; 51:2811-6. PubMed
  • Hiramatsu Y, Sekiguchi N, Hayashi M, Isshiki K, Yokota T, King GL, Loeken MR. Diacylglycerol production and protein kinase C activity are increased in a mouse model of diabetic embryopathy. Diabetes 2002; 51:2804-10. PubMed
  • Pani L, Horal M, Loeken MR. Rescue of neural tube defects in Pax-3-deficient embryos by p53 loss of function: implications for Pax-3- dependent development and tumorigenesis. Genes Dev 2002; 16:676-80. PubMed
  • Fine EL, Horal M, Chang TI, Fortin G, Loeken MR. Evidence that elevated glucose causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy. Diabetes 1999; 48:2454-62. PubMed
  • Cai J, Phelan SA, Hill AL, Loeken MR. Identification of Dep-1, a new gene regulated by the transcription factor Pax-3, as a marker for altered embryonic gene expression during diabetic pregnancy. Diabetes 1998; 47:1803-5. PubMed
  • Phelan SA, Loeken MR. Identification of a new binding motif for the paired domain of Pax-3 and unusual characteristics of spacing of bipartite recognition elements on binding and transcription activation. J Biol Chem 1998; 273:19153-9. PubMed
  • Hill AL, Phelan SA, Loeken MR. Reduced expression of pax-3 is associated with overexpression of cdc46 in the mouse embryo. Dev Genes Evol 1998; 208:128-34. PubMed
  • Phelan SA, Ito M, Loeken MR. Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis. Diabetes 1997; 46:1189-97. PubMed
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