Cyclin E, an activator of cyclin-dependent kinase 2 (Cdk2) is a positive activator of the G1-S phase transition in proliferating mammalian cells and therefore serves an important function during development and in replenishment of tissues. However, cyclin E is frequently overexpressed and deregulated in human malignancies, indicating that excessive or mistimed cyclin E-Cdk2 activation can promote oncogenesis. Yet little is known about the normal or pathological functions of cyclin E at the cellular or molecular level. This proposal seeks to investigate both functions of cyclin E through a variety of in vitro and in vivo approaches.
The first aim of the proposal focuses on the roles of cyclin E in promoting entry of cells into S phase. Standard molecular and cell biological approaches will be employed. We have also embarked on a proteomic strategy to identify new proteins relevant to the S- phase promoting function of cyclin E.
The second aim utilizes cell and molecular biological approaches to elucidate the mechanism(s) whereby cyclin E deregulation causes DNA damage and genomic instability, the most likely link to oncogenesis. In the third aim, cyclin E transgenic mouse carcinogenesis models are used to test the hypothesis of cyclin E- mediated genomic instability in vivo. This is critical, as most prior work has been carried out in cell culture models, which have only a limited relevance to human cancer. Finally, we are investigating the mechanism of cyclin E turnover, since cyclin E becomes deregulated when this process fails. Interestingly, the pathway that targets cyclin E for ubiquitin-mediated proteolysis also targets several other oncoproteins, underscoring its importance for oncogenesis. It is hoped that insights gained from understanding these fundamental mechanisms of oncogenesis will lead to new approaches to cancer prevention and therapy.
Cancer is a disease with tremendous health implications for the US and world. Yet, only limited progress has been made in curing most types of cancer. In part, this is because many mechanistic questions concerning the basic biology of cancer remain unanswered. This proposal seeks to address some of these unanswered questions.
|Teixeira, Leonardo K; Reed, Steven I (2016) Cdc6: Skin in the carcinogenesis game. Cell Cycle 15:313|
|del RincÃ³n, 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|
|Ekholm-Reed, Susanna; Goldberg, Matthew S; Schlossmacher, Michael G et al. (2013) Parkin-dependent degradation of the F-box protein Fbw7Î² promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1. Mol Cell Biol 33:3627-43|
|Bhaskaran, Nimesh; van Drogen, Frank; Ng, Hwee-Fang et al. (2013) Fbw7Î± and Fbw7Î³ collaborate to shuttle cyclin E1 into the nucleolus for multiubiquitylation. Mol Cell Biol 33:85-97|
|Teixeira, Leonardo K; Reed, Steven I (2013) Ubiquitin ligases and cell cycle control. Annu Rev Biochem 82:387-414|
|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|
|Liberal, Vasco; De Miguel, Maria P; Henze, Martha et al. (2010) Reduced spermatogonial proliferation and decreased fertility in mice overexpressing cyclin E in spermatogonia. Cell Cycle 9:4222-7|
|Best, D Hunter; Coleman, William B (2010) Liver regeneration by small hepatocyte-like progenitor cells after necrotic injury by carbon tetrachloride in retrorsine-exposed rats. Exp Mol Pathol 89:92-8|
Showing the most recent 10 out of 29 publications