Abstract

An intriguing characteristic of metastatic embryonal carcinoma, a type of germ cell tumor (GCT), is that they are able to differentiate to localized teratoma, which is made up of more mature, slower growing tissue of all three embryonic lineages, ectoderm, mesoderm, and endoderm. Differentiation of embryonal carcinoma (EC) is controlled by regulatory genes that mediate permanent phenotypic change. These regulatory genes are often transcriptional regulators that activate or repress patterns of gene expression that create the phenotypic change seen during stem cell differentiation. These transcription factors can not only mediate phenotypic maturation during a particular differentiation stage of GCT, but can also regulate expression of the transcription factors that are important in the next stage of differentiation. The goal of this grant is to increase understanding how the transcription factors present in the EC cell regulate the initial lineage decisions an EC cells makes as it first differentiates. The POU homeodomain protein Oct-4 and the Forkhead Box protein we isolated, FoxD3 (previously Genesis), are transcription factors preferentially expressed in EC cells. In the normal embryonic equivalent of EC cells, embryonic stem (ES) cells, downregulation of Oct-4 during gastrulation is essential for proper lineage development. We have previously found that Oct-4 can also act as a co-repressor to prevent FoxD3 from activating the promoters of the differentiation transcription factors FoxA1 and 2. This study will investigate the role of Oct-4 and FoxD3 in EC cell differentiation decisions in three specific aims. 1) The interacting domains between Oct-4 and FoxD3 will be mapped and their function analyzed in real time proteomics. 2) The biochemical mechanism by which Oct-4 represses lineage-specific transcriptional activation will be investigated. 3) How the repressor activity of Oct-4 mediates totipotentiality versus teratoma differentiation in EC cells will be studied.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102283-05
Application #
7253915
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mietz, Judy
Project Start
2003-09-11
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$236,453
Indirect Cost

  Institution

Name
University of New Mexico
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131

  Publications

Hromas, R; Williamson, E A; Fnu, S et al. (2012) Chk1 phosphorylation of Metnase enhances DNA repair but inhibits replication fork restart. Oncogene 31:4245-54
Williamson, Elizabeth A; Damiani, Leah; Leitao, Andrei et al. (2012) Targeting the transposase domain of the DNA repair component Metnase to enhance chemotherapy. Cancer Res 72:6200-8
Fnu, Sheema; Williamson, Elizabeth A; De Haro, Leyma P et al. (2011) Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining. Proc Natl Acad Sci U S A 108:540-5
Allen, Chris; Ashley, Amanda K; Hromas, Robert et al. (2011) More forks on the road to replication stress recovery. J Mol Cell Biol 3:4-12
Ponder, Jessica; Yoo, Byong Hoon; Abraham, Adedoyin D et al. (2011) Neoamphimedine circumvents metnase-enhanced DNA topoisomerase II? activity through ATP-competitive inhibition. Mar Drugs 9:2397-408
Kong, Kimi Y; Williamson, Elizabeth A; Rogers, Jason H et al. (2009) Expression of Scl in mesoderm rescues hematopoiesis in the absence of Oct-4. Blood 114:60-3
Wray, Justin; Williamson, Elizabeth A; Sheema, Sheema et al. (2009) Metnase mediates chromosome decatenation in acute leukemia cells. Blood 114:1852-8
Williamson, Elizabeth A; Farrington, Jacqueline; Martinez, Leah et al. (2008) Expression levels of the human DNA repair protein metnase influence lentiviral genomic integration. Biochimie 90:1422-6
Williamson, Elizabeth A; Rasila, Kanwaldeep Kaur; Corwin, Lori Kwan et al. (2008) The SET and transposase domain protein Metnase enhances chromosome decatenation: regulation by automethylation. Nucleic Acids Res 36:5822-31
Guo, Ying; Mantel, Charlie; Hromas, Robert A et al. (2008) Oct-4 is critical for survival/antiapoptosis of murine embryonic stem cells subjected to stress: effects associated with Stat3/survivin. Stem Cells 26:30-4

Showing the most recent 10 out of 15 publications