The cell cycle regulatory protein cyclin E is overexpressed in many different cancers. The level of cyclin E in tumors is independent of the proliferation index, suggesting that its overexpression is a cause rather than an effect of tumorigenesis. In normal cells, cyclin E MRNA and protein are expressed briefly during the transition from the first gap phase (G1) to the DNA synthesis phase (S) when it binds to and activates its kinase partner, cyclin-dependent kinase 2 (cdk2). In cancer cells, high levels of cyclin E throughout the cell cycle result in sustained cdk2 activity and uncontrolled cell growth. Alterations in cyclin E expression include increased protein stability, increased stability and overexpression of mRNA and gene amplification. Our long-term goal is to define the mechanisms leading to increased cyclin E mRNA and protein stability in human cancers. The purpose of this proposal is to use Xenopus laevis embryos, a system that naturally overexpresses cyclin E, to identify novel pathways that lead to cyclin E overexpression. As in cancer cells, cyclin E overexpression in Xenopus embryos is due to increased mRNA and protein stability; however, cdk2 activity appears to be regulated despite high cyclin E levels. In addition, cyclin E protein is destabilized when cells begin the adult somatic cell cycle. We will use the Xenopus system to determine 1) how cyclin E mRNA is stabilized, 2) how high cyclin E protein levels are maintained, and 3) how cyclin E protein is destabilized at the onset of the adult cell cycle. Lastly, 4) we will ask if mechanisms regulating cyclin E are conserved between Xenopus embryos and human cancer cell lines. Once mechanisms are identified, Xenopus represents an ideal in vivo and in vitro system to identify therapeutic compounds that target elevated cyclin E and thus cdk2 activity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095898-02
Application #
6786070
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (O1))
Program Officer
Spalholz, Barbara A
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$300,375
Indirect Cost
Name
University of New Mexico
Department
Physiology
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Brandt, Yekaterina I; Mitchell, Therese; Smolyakov, Gennady A et al. (2015) Quantum dot assisted tracking of the intracellular protein Cyclin E in Xenopus laevis embryos. J Nanobiotechnology 13:31
Guo, Xun; Connick, Melanie C; Vanderhoof, Jennifer et al. (2015) MicroRNA-16 modulates HuR regulation of cyclin E1 in breast cancer cells. Int J Mol Sci 16:7112-32
Guo, Xun; Wu, Yuehan; Hathaway, Helen J et al. (2012) Microenvironmental control of the breast cancer cell cycle. Anat Rec (Hoboken) 295:553-62
Wu, Yuehan; Guo, Xun; Brandt, Yekaterina et al. (2011) Three-dimensional collagen represses cyclin E1 via ?1 integrin in invasive breast cancer cells. Breast Cancer Res Treat 127:397-406
Brandt, Yekaterina; Mitchell, Therese; Wu, Yuehan et al. (2011) Developmental downregulation of Xenopus cyclin E is phosphorylation and nuclear import dependent and is mediated by ubiquitination. Dev Biol 355:65-76
Sheets, M D; Fritz, B; Hartley, R S et al. (2010) Polyribosome analysis for investigating mRNA translation in Xenopus oocytes, eggs and embryos. Methods 51:152-6
Guo, Xun; Wu, Yuehan; Hartley, Rebecca S (2010) Cold-inducible RNA-binding protein contributes to human antigen R and cyclin E1 deregulation in breast cancer. Mol Carcinog 49:130-40
Almeida, Alexandra D; Wise, Helen M; Hindley, Christopher J et al. (2010) The F-box protein Cdc4/Fbxw7 is a novel regulator of neural crest development in Xenopus laevis. Neural Dev 5:1
Guo, Xu; Wu, Yuehan; Hartley, Rebecca S (2009) MicroRNA-125a represses cell growth by targeting HuR in breast cancer. RNA Biol 6:575-83
Guo, Xun; Gourronc, Francoise; Audic, Yann et al. (2008) ElrA and AUF1 differentially bind cyclin B2 mRNA. Biochem Biophys Res Commun 377:653-7

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