- Frank B. Tyler Professor of Cancer Research
Role of APC tumor suppressor protein in normal colon and in cancer.
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.
Selected Publications —
- (2020) Gomez, C.L. and Neufeld, K.L. Elevated Adenomatous Polyposis Coli in Goblet Cells is Associated with Inflammation in Mouse and Human Colon. Experimental Physiology 105:2154-2167. PMID: 33150708
- (2020) Chiremba, T.T. and Neufeld, K.L. Constitutive Musashi1 expression impairs mouse postnatal development and intestinal homeostasis. Molecular Biology of the Cell 32:28-44. PMID: 33175598
- (2020) Rudeen, A. J., Douglas, J. T., Xing, M., McDonald, H., Lamb, A. L., and Neufeld, K. L. The 15-Amino Acid Repeat Region of Adenomatous Polyposis Coli Is Intrinsically Disordered and Retains Conformational Flexibility upon Binding β-Catenin. Biochemistry 59:4039-4050. PMID: 32941008
- (2020) Lan L, Liu J, Xing M, Smith AR, Wang J, Wu X, Appelman C, Li K, Roy A, Gowthaman R, Karanicolas J, Somoza AD, Wang CCC, Miao Y, De Guzman R, Oakley BR, Neufeld K.L., Xu L. Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction. Cancers 12:2221. PMID: 32784494
- (2020) Parker, T.W., Rudeen, A.J., Neufeld, K.L. Oncogenic Serine 45-Deleted β-Catenin Remains Susceptible to Wnt Stimulation and APC Regulation in Human Colonocytes. Cancers 12:2114. PMID: 32751567
- (2020) Efimova, N., Yang, C., Chia, J. X., Li, N., Lengner, C. J., Neufeld, K. L. and Svitkina, T. M. "Branched actin networks are assembled on microtubules by adenomatous polyposis coli for targeted membrane protrusion". Journal of Cell Biology 219: e202003091. PMID: 32597939
- (2020) Parker, TW and Neufeld, KL. APC controls Wnt-induced β-catenin destruction complex recruitment in human colonocytes. Scientific Reports 10:2957. PMID: 7031393Top 100 downloaded cell and molecular biology articles in 2020
- (2018) Lan L, Liu H, Smith AR, Appelman C, Yu J, Larsen S, Marquez RT, Wu X, Liu FY, Gao P, Gowthaman R, Karanicolas J, De Guzman RN, Rogers S, Aubé J, Neufeld KL, Xu L. Natural product derivative Gossypolone inhibits Musashi family of RNA-binding proteins. BMC Cancer 18:809 PMID: 30097032
- (2017) Gao, F.J., Shi, L, Hines, T, Hebbar, S, Neufeld, KL, Smith, DL. Insulin signaling regulates a functional interaction between adenomatous polyposis coli and cytoplasmic dynein. Molecular Biology of the Cell 28:587-599. PMID:28057765
- (2015) Smith A.R., Marquez R.T., Tsao W.C., Pathak S, Roy A, Ping J, Wilkerson B, Lan L, Meng W, Neufeld K.L., Sun X.F., Xu L. Tumor Suppressive microRNA-137 Negatively Regulates Musashi-1 in Colorectal Cancer. Oncotarget6: 12558-73. PMID: 25940441
- (2015) Lan L., Appelman C., Smith A.R., Yu J., Larsen S., Marquez R.T., Liu H., Wu X., Gao P., Roy A., Anbanandam A., Gowthaman R., Karanicolas J., De Guzman R.N., Rogers S., Aubé J., Ji M., Cohen R.S., Neufeld K.L., Xu L. Natural product (–)-gossypol inhibits colon cancer cell growth by targeting RNA-binding protein Musashi-1. Molecular Oncology 9:1406-1420. PMID: 25933687
- (2015) Zeineldin, M. & Neufeld, K.L. New insights from animal models of colon cancer: Inflammation control as a new facet on the tumor suppressor APC gem. Gastrointestinal Cancer: Targets and Therapy2015:5: 39—52
- (2014) Zeineldin, M., Miller, M, Sullivan, R. & Neufeld, K.L. Nuclear adenomatous polyposis coli suppresses colitis-associated tumorigenesis in mice. Carcinogenesis 35:1881-1890. PMID: 24894865
- (2014) Zeineldin, M. Jensen, D., Paranjape, S.R., Parelkar, N. K., Jokar, I, Vielhauer, G. A. & Neufeld, K.L. Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis. Genetics 97:1365-1376. PMID: 24913681F1000Prime Recommendations as being of special significance in its field
- (2013) Zeineldin, M. & Neufeld, K.L. Understanding phenotypic variation in rodent models with germline Apc mutations. Cancer Research 73: 2389-2399. PMID: 23580574
- (2013) Zeineldin, M. & Neufeld, K.L. More than two decades of Apc modeling in rodents. Biochim Biophys Acta: Reviews on Cancer 1836:80-89. PMID: 23333833
- (2012) Zeineldin, M. and Neufeld, K. Isolation of Epithelial Cells from Mouse Gastrointestinal Tract for Western Blot or RNA Analysis. bio-protocol 2: e292. PMID: 27148556
- (2012) Zeineldin, M., Cunningham, J., McGuinness, W., Alltizer, P., Cowley, B., Blanchat, B, Xu, W., Pinson, D. & Neufeld, K.L. A knock-in mouse model reveals roles for nuclear Apc in cell proliferation, Wnt signal inhibition and tumor suppression. Oncogene 31: 2423-2437. PMID: 21996741
- (2011) Spears, E & Neufeld, K. L. A novel double-negative feedback loop between Adenomatous Polyposis coli and musashi1 in colon epithelia. Journal of Biological Chemistry 286: 4946-4950. PMID: 21199875
- (2010) Ashton GH, Morton JP, Myant K, Phesse TJ, Ridgway RA, Marsh V, Wilkins JA, Athineos D, Muncan V, Kemp R, Neufeld K, Clevers H, Brunton V, Winton DJ, Wang X, Sears RC, Clarke AR, Frame MC, Sansom OJ. Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Developmental Cell 19(2): 259-269. PMID: 20708588
- (2010) Wang, Y., Coffey, R, Osheroff, N., and K.L.Neufeld. Topoisomerase II alpha Binding Domains of Adenomatous Polyposis Coli Influence Cell Cycle Progression and Aneuploidy. PLoS One 5: e9994; PMID: 20368985
- (2009) Wang, Y., Azuma, Y., Friedman, D. B., Coffey, R., and K. L. Neufeld. Novel Association of APC with Intermediate Filaments Identified using a New Versatile APC Antibody. BMC Cell Biology 10:75-88. PMID: 19845967
- (2008) Wang, Y., Azuma, Y., Moore, D., Osheroff, N., and K. L. Neufeld. Interaction between Tumor Suppressor APC and Topoisomerase II alpha: Implications for the G2/M Transition. Molecular Biology of the Cell 19:4076-4085. PMID: 18632987
- (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. (2009) Advanced Experimental Medical Biology 656:13-29. PMID: 19928349
- (2004) Satterwhite, D.J. and K. L. Neufeld. TGF-beta targets the Wnt pathway components, APC and beta-catenin, as Mv1Lu cells undergo cell cycle arrest. Cell Cycle 3:1069-73. PMID: 15280661
- (2002) Anderson, C, K. L. Neufeld and White, R. Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon. Proceedings of the National Academy of Science. USA99: 8683-8688. PMID: 12072559
- (2001) Liu, J., Stevens, J., Rote, C.A., Yost, J. H., Hu, Y. Neufeld, K. L., White, R., and N. Matsunami. Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Molecular Cell 7:927-936. PMID: 11389840
- (2001) Zhang, F., White, R., and K. L. Neufeld. Cell density and phosphorylation control the subcellular localization of adenomatous polyposis coli. Molecular and Cellular Biology 21:8143-8156. PMID: 11689703
- (2000) Neufeld, K. L., Nix, D. A., Bogerd, H, Kang, Y., Beckerle, M. C., Cullen, B. R., and R. L. White. Adenomatous Polyposis Coli protein contains two nuclear export signals and shuttles between nucleus and cytoplasm. Proceedings of the National Academy of Science. USA. 97: 12085-12090. PMID: 11035805
- (2000) Satterwhite, D.J., White, R, Matsunami, N., and K. L. Neufeld. Inhibition of Topoisomerase II alpha Expression by Transforming Growth Factor-b1 is Abrogated by the Papillomavirus E7 Protein. Cancer Research 60: 6989-94. PMID: 11156401
- (2000) Zhang, F., White, R., and K. L. Neufeld. Phosphorylation near nuclear localization signal regulates nuclear import of adenomatous polyposis coli protein. Proceedings of the National Academy of Science. USA 97: 12577-12582. PMID: 11050185
- (2000) Neufeld, K. L., Zhang, F., Cullen, B. R. and R. L. White. APC-mediated down-regulation of beta-Catenin activity involves nuclear sequestration and nuclear export. EMBO Report 1:519- 523. PMID: 11263497
- (1999) 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. APC1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. Genes and Development 13: 1309-1321. PMID: 10346819
- (1997) Neufeld, K. L. and R. White. Nuclear and cytoplasmic localizations of adenomatous polyposis coli protein. Proceedings of the National Academy of Science. USA 94: 3034-3039. PMID: 9096341
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