Cyclin E, as a positive regulator of the cyclin-dependent kinase, Cdk2, is a key regulator of cell cycle progression. It can also become, when deregulated, a factor in oncogenesis. However, neither the molecular mechanisms whereby cyclin E stimulates cell cycle progression nor those whereby it participates in oncogenesis have been elucidated. This proposal seeks to investigate the function and regulation of cyclin E in both contexts in normal and tumor-derived human breast epithelial cells, the rationale being that information gained is likely to have eventual implications for prevention, diagnosis and therapy of breast cancer. The research plan consists of four specific aims. The first addresses the issue of cyclin E essentiality and function by eliminating cyclin E expression via novel antisense oligonucleotide technology. The second specific aim, also using antisense oligonucleotide technology, investigates the mechanisms whereby breast epithelial cells regulate cyclin E-associated Cdk2 kinase activity to maintain an appropiate proliferative response. The third specific aim directly addresses the mechanism whereby cyclin E deregulation leads to malignant transformation. Tissue culture models are used to investigate the relationship between cyclin E overexpression and genetic instability, whereas a transgenic mouse model is used to directly probe the mechanisms whereby cyclin E deregulation causes mammary carcinogenesis. Finally, the fourth specific aim seeks to investigate whether deregulation of cyclin E proteolysis or maturation play a role in cyclin E accumulation under conditions associated with oncogenesis. Because reagents and technology are already available for carrying out most of these studies, it is anticipated that rapid progress can be achieved on all research avenues proposed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078343-04
Application #
6376811
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1998-08-01
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
4
Fiscal Year
2001
Total Cost
$263,440
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Mu, Ruiling; Tat, John; Zamudio, Robert et al. (2017) CKS Proteins Promote Checkpoint Recovery by Stimulating Phosphorylation of Treslin. Mol Cell Biol 37:
Teixeira, Leonardo K; Reed, Steven I (2016) Cdc6: Skin in the carcinogenesis game. Cell Cycle 15:313
del Rincón, S V; Widschwendter, M; Sun, D et al. (2015) Cks overexpression enhances chemotherapeutic efficacy by overriding DNA damage checkpoints. Oncogene 34:1961-7
Teixeira, Leonardo K; Wang, Xianlong; Li, Yongjiang et al. (2015) Cyclin E deregulation promotes loss of specific genomic regions. Curr Biol 25:1327-33
Sandhu, Rupninder; Rivenbark, Ashley G; Mackler, Randi M et al. (2014) Dysregulation of microRNA expression drives aberrant DNA hypermethylation in basal-like breast cancer. Int J Oncol 44:563-72
Teixeira, Leonardo K; Reed, Steven I (2013) Ubiquitin ligases and cell cycle control. Annu Rev Biochem 82:387-414
Bhaskaran, Nimesh; van Drogen, Frank; Ng, Hwee-Fang et al. (2013) Fbw7? and Fbw7? collaborate to shuttle cyclin E1 into the nucleolus for multiubiquitylation. Mol Cell Biol 33:85-97
Ekholm-Reed, Susanna; Goldberg, Matthew S; Schlossmacher, Michael G et al. (2013) Parkin-dependent degradation of the F-box protein Fbw7? promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1. Mol Cell Biol 33:3627-43
Best, D Hunter; Butz, Genelle M; Coleman, William B (2010) Cytokine-dependent activation of small hepatocyte-like progenitor cells in retrorsine-induced rat liver injury. Exp Mol Pathol 88:7-14

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