Faculty

Our long-range goal is to reveal the underlying mechanisms for growth control of normal intestinal tissue, explaining how disruption of this normal state leads to tumor formation. Epithelial cells lining a healthy human colon continuously renew with a highly regulated pattern of cell division. Colonocytes originate from stem cells located at the base of the colonic crypt, approximately 30 cells below the luminal surface. In the course of its short life, a colonocyte moving toward the luminal surface will divide a few times, differentiate, undergo apoptosis, and ultimately be shed into the lumen. Thus, an isolated colon crypt represents an elegant developmental system, with stem cells originating at the base and progressively more differentiated cells moving up towards the lumen of the colon. Determining how the normal colon maintains this exquisite control of proliferation, differentiation, and apoptosis is fundamental to understanding carcinogenesis.

The tumor suppressor gene Adenomatous Polyposis Coli (APC) is mutated early in the progression of most colon cancers. APC was initially thought to be exclusively cytoplasmic, functioning to eliminate cytoplasmic pools of the beta-catenin oncogene. It is becoming evident that APC has a broader localization spectrum than first suggested, with the potential for participation in multiple cellular processes. We have identified APC in both the cytoplasm and nucleus of both tissue culture cells and intact crypts from normal human colon. Our analysis of APC protein localization and function implicates APC protein as a central player in a signaling pathway that controls colonic epithelial cell proliferation. APC shuttling between the nucleus and cytoplasm is a key component of this signaling pathway.

We are currently focused on three major downstream consequences of the APC signaling pathway. An interaction between APC and DNA topoisomerase IIα appears to be involved in regulation of cell cycle progression. APC interaction with the stem cell marker musashi might contribute to stem cell homeostasis APC’s role in DNA repair and stress response is also being investigated. In addition, the role of nuclear APC is being investigated in two normal contexts—mouse embryonic stem (ES) cells and the whole mouse.

Representative Publications

• (2008) K. L. Neufeld. “Nuclear Functions of APC” published as chapter in the book Adenomatous polyposis coli protein by Landes Bioscience, Inke Näthke and Brooke McCartney editors.
• (2008) Wang, Y., Azuma, Y., Moore, D., Osheroff, N., and K. L. Neufeld. “Interaction between Tumor Suppressor APC and Topoisomerase IIα: Implications for the G2/M Transition” Mol. Biol. Cell 19:4076–4085
• Satterwhite, D.J. and K. L. Neufeld. 2004 TGF-beta targets the Wnt pathway components, APC and beta-catenin, as Mv1Lu cells undergo cell cycle arrest. Cell Cycle 3(8):1069–73.
• Anderson, C, K. L. Neufeld and White, R. 2002 Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon. Proc. Natl. Acad. Sci. USA. 99: 8683–8688.
• Zhang, F., White, R., and K. L. Neufeld. 2001 Cell density and phosphorylation control the subcellular localization of APC, Mol. Cell Biol. 21:8143–8156.
• Liu, J., Stevens, J., Rote, C.A., Yost, J. H., Hu, Y. Neufeld, K. L., White, R., and N. Matsunami. 2001 Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Mol. Cell. 7:927–936.
• Neufeld, K. L., Zhang, F., Cullen, B. R. and R. L. White. 2000 APC-mediated down-regulation of beta-Catenin activity involves nuclear sequestration and nuclear export. EMBO Reports. 6: 519–523.
• Zhang, F., White, R., and K. L. Neufeld. 2000 APC protein possesses two functional nuclear localization signals, with phosphorylation at an adjacent PKA site negatively regulating nuclear import. Proc. Natl. Acad. Sci. USA. 97: 12577–12582.
• Satterwhite, D.J., White, R, Matsunami, N., and K. L. Neufeld. 2000 Inhibition of Topoisomerase II-alpha Expression by Transforming Growth Factor-beta1 is Abrogated by the Papillomavirus E7 Protein. Cancer Res. 60: 6989–94.
• Neufeld, K. L., Nix, D. A., Bogerd, H, Kang, Y., Beckerle, M. C., Cullen, B. R., and R. L. White. 2000 Adenomatous Polyposis Coli protein contains two nuclear export signals and shuttles between nucleus and cytoplasm. Proc. Natl. Acad. Sci. USA. 97: 12085–12090.
• Smits, R., Kielman, M., Breukel, C., Jagmohan-Changur, S., Zurcher, C., Neufeld, K., Hofland, N, van Dijk, J., White, R., Edelmann, W., Kucherlapati, P., Khan, M, and R. Fodde. 1999 APC1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. Genes Dev. 13: 1309–1321.
• Neufeld, K. L. and R. White. 1997 Cytoplasmic and nuclear localizations of adenomatous polyposis coli protein. Proc. Natl. Acad. Sci. USA. 94: 3034–3039.

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