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Nywana Sizemore, Ph.D.
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Area of general research interest:
Role of aberrant signal transduction by AKT and IκB kinase in controlling gene expression, oncogenesis, and apoptosis in colorectal and other cancers.
Current programs:
- Define the role and molecular mechanism of AKT in regulating of the IKK activity towards the nuclear factor kappa B (NFκB) and β-catenin transcription factors
- Define the functional and structural requirements of IκB kinase (IKK) to modulate the NFkB and β-catenin transcription factors
- Identification of changes in the phosphorylation and transcriptional activity of NFκB and β-catenin induced by IKK
- Identification of NFκB- and β-catenin-dependent genes involved in colorectal cancer development and progression
- Identification of novel molecular targets of IKK action
Investigators:
- Kristi Allen, Ph.D., Research Fellow
- Natalia Lerner, B.S., Senior Research Technologist
- Roxana Niculaita, M.D., Graduate Student
Collaborators:
- Graham Casey, Ph.D., Department of Cancer Biology, The Cleveland Clinic Foundation, Cleveland Ohio
- George R. Stark, Ph.D., Department of Molecular Genetics, The Cleveland Clinic Foundation, Cleveland Ohio
Brief Description:
Our laboratory has delineated that the phosphatidylinositol 3′ kinase (PI3κ)/AKT/IκB kinase (IKK) cell survival pathway positively regulates and the PTEN tumor suppressor pathway negatively regulates nuclear factor κB (NFκB) and β-catenin, both important transcriptional regulators in colorectal cancer (CRC).
The NFκB and β-catenin pathways are major contributors to the deregulated growth, resistance to apoptosis, and propensity to metastasize observed in many cancers. We have shown that many CRC cell lines and tissues show constitutive activation of the IKK pathway and that maintenance of this activity is necessary for CRC cell proliferation, angiogenic/metastatic gene expression, and resistance to apoptosis induced by chemotherapeutics.
The focus of our current studies is on the role and signaling mechanisms of AKT and PTEN in controlling the activity of IKK towards these transcription factors, as well as the roles these transcription factors play in controlling tumorigenesis and apoptosis. Additionally, we have identified a new tumor suppressor gene critical for a specific subset of CRC which acts analogous to the adenomatous polyposis coli (APC) gene by inhibiting Wnt/β-catenin signal transduction and maintaining efficient cellular migration.
The studies of this new CRC tumor suppressor and on the identification of novel molecular targets of IKK action involved in cellular signaling and the evolution of cancer are ongoing.
Key References:
Sizemore, N., Gangarosa L.M., Graves-Deal, R., Oldham, S.M., Der, C.J. and Coffey, R.J. (1997). A Raf-independent EGF receptor autocrine loop is necessary for Ras-transformation of rat intestinal epithelial cells. J. Biol. Chem. 272, 18926-18931.
Sizemore, N., Cox A.D., Barnard J.A., Oldham S.M., Reynolds E.R., Der C.J., and Coffey, R.J. (1999). Pharmacological inhibition of Ras-transformed epithelial cell growth is linked to down-regulation of epidermal growth factor-related peptides. Gastroenterology 117, 567-76.
Sizemore, N., Leung, S., and Stark, G.R. (1999). Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF- kappaB p65/RelA subunit. Mol. Cell. Biol. 19, 4798-4805.
Rani, M.R.S., Asthagiri, A.R., Singh, A., Sizemore, N., Sathe, S.S., Li, X., DiDonato, J.D., Stark, G.R., and Ransohoff, R.M. (2001). A role for NF-kappa B in the induction of beta-R1 by interferon- beta. J. Biol. Chem. 276, 44365-44368.
Rani, M.R.S., Hibbert, L., Sizemore, N., Stark, G.R., and Ransohoff, R.M. (2002). Requirement of phosphoinositide 3-kinase and Akt for interferon- [beta]-mediated induction of the [beta]-R1 (SCYB11) gene. J. Biol. Chem. 277, 38456-38461.
Sizemore, N., Lerner, N., Dombrowski, N., Sakurai, H., and Stark, G.R. (2002). Distinct roles of the I kappa B kinase alpha and beta subunits in liberating nuclear factor kappa B (NF kappa B) from I kappa B and in phosphorylating the p65 subunit of NF-kappa B. J. Biol. Chem. 277, 3863-3869.
Lee, J.Y., Ye, J.P., Gao, Z.G., Youn, H.S., Lee, W.H., Zhao, L., Sizemore, N., and Hwang, D.H. (2003). Reciprocal modulation of toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J. Biol. Chem. 278, 37041-37051.
Sathe, S.S., Sizemore, N., Li, X., Vithalani, K., Commane, M., Swiatkowski, S.M., and Stark, G.R. (2004). Mutant human cells with constitutive activation of NF-{kappa}B. Proc. Natl. Acad. Sci. U. S. A. 101, 192-197.
Sizemore, N., Agarwal, A., Das, K., Lerner, N., Sulak, M., Rani, S., Ransohoff, R., Shultz, D., and Stark, G.R. (2004). Inhibitor of kappaB kinase is required to activate a subset of interferon gamma-stimulated genes. Proc. Natl. Acad. Sci. U. S. A. 101, 7994-7998.
Agarwal, A., Das, K., Lerner, N., Sathe, S., Cicek, M., Casey, G., and Sizemore, N. (2005). The AKT/I kappa B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-kappa B and beta-catenin. Oncogene 24, 1021-1031.
Cicek, M., Fukuyama, R., Welch, D.R., Sizemore, N., and Casey, G. (2005). Breast cancer metastasis suppressor 1 inhibits gene expression by targeting nuclear factor-kappaB activity. Cancer Res. 65, 3586-3595.
Horinaga, M., Fukuyama, R., Nishiyama, T., Harsch, K.M., Cicek, M., Heston, W., Sizemore, N., Casey, G., and Larchian, W. (2005). Novel enhanced lung-colonizing variant of murine MBT-2 bladder cancer cells. Urology 66, 676-681.
Fukuyama R, et al. Role of IKK and oscillatory NFκB kinetics in MMP-9 gene expression and chemoresistance to 5-fluorouracil in RKO colorectal cancer cells. Mol Carcinog 2007;46:402-13.