Education & Training
- Postdoctoral Fellow
- Howard Hughes Medical Institute, University of California, San Diego, 2008
- University of Montreal, Canada, 2003
Areas of Interests
- Research Interest
- Cell Cycle Regulation, Cancer and Metastasis
Cell Cycle Regulation, Cancer and Metastasis
The cell cycle is the sequence of events that cells use to faithfully replicate their DNA and segregate their duplicated chromosomes equally between two daughter cells. Cyclins regulate the cell cycle positively by binding to and activating cyclin-dependent kinases (Cdks). Phosphorylation of specific targets by cyclin-Cdk complexes set in motion different cellular processes that drive the cell cycle in a timely and highly regulated manner. Cdks are negatively regulated by CKIs (Cdk inhibitors, IKN4 and Cip/Kip) that physically associate with and inhibit their activity to promote cell cycle arrest.
Cells commit to proliferate, or not, during the G1 phase of the cell cycle. The decision to enter the cell cycle from the resting Go phase is influenced by the summation of extracellular signals, such as nutrients and mitogens. The point in G1 at which commitment occurs, when the cell no longer requires growth factors to complete cell division, is termed the restriction point. Once cells pass this point, they are irreversibly committed to complete the cycle. This complex molecular checkpoint, that impinges on the cell cycle apparatus at many levels, remains poorly understood. However, it is well recognized that loss of the G1/S checkpoint(s) is an important step in the initiation of cancer. We want to better define the signaling pathways that govern the G1 to S phase progression for a better understanding of cancer and the development of novel therapeutics.
We are particularly interested in the cyclin/cdk inhibitor p27Kip1. This protein was first identified as a negative regulator of G1 phase cell cycle progression. Based on tumor predisposition of p27Kip1 null mice, p27Kip1 is regarded as a nuclear tumor suppressor. However, human malignancies rarely select for deletion/inactivation of the p27Kip1 gene, a hallmark of tumor suppressor genes. Instead, p27Kip1 is often found either absent from the nucleus (and cell) or relocalized to the cytoplasm in some aggressive, metastatic malignancies. We found that p27Kip1 was strongly present in the cytoplasm of human invasive and metastatic melanomas. Using in vivo experimental models of metastasis, we showed that cytoplasmic p27Kip1 dramatically increases the metastatic potential of melanoma. Cytoplasmic p27Kip1 is also observed in 41% of human breast cancers and this is correlated with poor patient prognosis.
Projects in the lab:
- Development of a transgenic mouse model to study the role of cytoplasmic p27 in breast cancer.
- Live cell imaging of mammary epithelial cells in 3-D cultures as a model to study the role of cell cycle regulators in breast cancer.
- Identification and characterization of novel mammalian cyclins involved in G1/S progression of the cell cycle.
- Castle CD, Sardana R, Dandekar V, Borgianini V, Johnson AW, and Denicourt C. (2013) Las1 interacts with Grc3 polynucleotide kinase and is required for ribosome synthesis in Saccharomyces cerevisiae. Nucleic Acids Research. 41:1135-1150.
- Castle CD, Cassimere EK, and Denicourt C. (2012) Las1L interacts with the mammalian Rix1 complex to regulate ribosome biogenesis. Mol. Biol. Cell. 23:716-728.
- Castle CD, Sardana R, Dandekar V, Borgianini V, Johnson AW, and Denicourt C. (2012) Las1 interacts with Grc3 polynucleotide kinase and is required for ribosome synthesis in Saccharomyces cerevisiae. Nucleic Acids Res. DOI: 10.1093/nar/gks1086.
- Castle CD, Cassimere EK, Lee J, and Denicourt C. (2010). Las1L is a nucleolar protein required for cell proliferation and ribosome biogenesis. Mol Cell Biol 30, 4404-4414.
- Denicourt C, Saenz CC, Datnow B, Cui XC, and Dowdy SF. (2007). Relocalized p27Kip1 Tumor Suppressor Functions as a Cytoplasmic Metastatic Oncogene in Melanoma. Cancer Res. 67:9238-9243.
- Denicourt C, Legault P, McNabb FA, and Rassart E. (2007). Human and mouse cyclin D2 splice variants: Transforming activity and subcellular localization. Oncogene 27:1253-1262.
- Snyder EL, Saenz CC, Denicourt C, Meade BR, Cui XS, Kaplan IM, and Dowdy SF. (2005). Enhanced targeting and killing of tumor cells expressing the CXC chemokine receptor 4 by transducible anticancer peptides. Cancer Res. 65:10646-10650.
- Denicourt C, and Dowdy SF. (2004). Cip/Kip proteins: more than just CDKs inhibitors. Genes & Dev. 18:851-855.