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http://dx.doi.org/10.4062/biomolther.2014.084

Caenorhabditis elegans: A Model System for Anti-Cancer Drug Discovery and Therapeutic Target Identification  

Kobet, Robert A. (Department of Medicine, Department of Oncology, Division of Hematology/Oncology, Brody School of Medicine, East Carolina University)
Pan, Xiaoping (Department of Biology, East Carolina University)
Zhang, Baohong (Department of Biology, East Carolina University)
Pak, Stephen C. (Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC)
Asch, Adam S. (Department of Medicine, Department of Oncology, Division of Hematology/Oncology, Brody School of Medicine, East Carolina University)
Lee, Myon-Hee (Department of Medicine, Department of Oncology, Division of Hematology/Oncology, Brody School of Medicine, East Carolina University)
Publication Information
Biomolecules & Therapeutics / v.22, no.5, 2014 , pp. 371-383 More about this Journal
Abstract
The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer.
Keywords
Caenorhabditis elegans; Wnt; Notch; Ras; Cancer stem cells; Drug screening;
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1 Towatari, M., Ciro, M., Ottolenghi, S., Tsuzuki, S. and Enver, T. (2004) Involvement of mitogen-activated protein kinase in the cytokineregulated phosphorylation of transcription factor GATA-1. Hematol. J. 5, 262-272.   DOI
2 Vaid, S., Ariz, M., Chaturbedi, A., Kumar, G. A. and Subramaniam, K. (2013) PUF-8 negatively regulates RAS/MAPK signalling to promote differentiation of C. elegans germ cells. Development 140, 1645-1654.   DOI   ScienceOn
3 Visvader, J. E. and Lindeman, G. J. (2012) Cancer stem cells: current status and evolving complexities. Cell stem cell 10, 717-728.   DOI
4 Morgan, C. T., Lee, M. H. and Kimble, J. (2010) Chemical reprogramming of Caenorhabditis elegans germ cell fate. Nat. Chem. Biol. 6, 102-104.   DOI
5 Nadarajan, S., Govindan, J. A., McGovern, M., Hubbard, E. J. and Greenstein, D. (2009) MSP and GLP-1/Notch signaling coordinately regulate actomyosin-dependent cytoplasmic streaming and oocyte growth in C. elegans. Development 136, 2223-2234.   DOI
6 Nusse, R., Fuerer, C., Ching, W., Harnish, K., Logan, C., Zeng, A., ten Berge, D. and Kalani, Y. (2008) Wnt signaling and stem cell control. Cold Spring Harb. Symp. Quant. Biol. 73, 59-66.   DOI
7 Nykamp, K., Lee, M. H. and Kimble, J. (2008) C. elegans La-related protein, LARP-1, localizes to germline P bodies and attenuates Ras-MAPK signaling during oogenesis. RNA 14, 1378-1389.   DOI   ScienceOn
8 O'Reilly, L. P., Luke, C. J., Perlmutter, D. H., Silverman, G. A. and Pak, S. C. (2014) C. elegans in high-throughput drug discovery. Adv. Drug Deliv. Rev. 69-70, 247-253.   DOI
9 Okabe, H., Lee, S. H., Phuchareon, J., Albertson, D. G., McCormick, F. and Tetsu, O. (2006) A critical role for FBXW8 and MAPK in cyclin D1 degradation and cancer cell proliferation. PLoS One 1, e128.   DOI
10 Pepper, A. S., Killian, D. J. and Hubbard, E. J. (2003a) Genetic analysis of Caenorhabditis elegans glp-1 mutants suggests receptor interaction or competition. Genetics 163, 115-132.
11 Pepper, A. S., Lo, T. W., Killian, D. J., Hall, D. H. and Hubbard, E. J. (2003b) The establishment of Caenorhabditis elegans germline pattern is controlled by overlapping proximal and distal somatic gonad signals. Dev. Biol. 259, 336-350.   DOI
12 Petcherski, A. G. and Kimble, J. (2000) LAG-3 is a putative transcriptional activator in the C. elegans Notch pathway. Nature 405, 364-368.   DOI
13 Phillips, B. T., Kidd, A. R., 3rd, King, R., Hardin, J. and Kimble, J. (2007) Reciprocal asymmetry of SYS-1/beta-catenin and POP-1/ TCF controls asymmetric divisions in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 104, 3231-3236.   DOI
14 Reedijk, M. (2012) Notch signaling and breast cancer. Adv. Exp. Med. Biol. 727, 241-257.   DOI   ScienceOn
15 Reya, T. and Clevers, H. (2005) Wnt signalling in stem cells and cancer. Nature 434, 843-850.   DOI   ScienceOn
16 Ristorcelli, E. and Lombardo, D. (2010) Targeting Notch signaling in pancreatic cancer. Expert Opin. Ther. Targets 14, 541-552.   DOI
17 Saxena, N., Lahiri, S. S., Hambarde, S. and Tripathi, R. P. (2008) RAS: target for cancer therapy. Cancer Invest. 26, 948-955.   DOI
18 Lee, M. H., Cha, D. S., Mamillapalli, S. S., Kwon, Y. C. and Koo, H. S. (2014) Transgene-mediated co-suppression of DNA topoisomerase-1 gene in Caenorhabditis elegans. Int. Biochem. Mol. Biol. 5, 11-20.
19 Lee, M. H., Ohmachi, M., Arur, S., Nayak, S., Francis, R., Church, D., Lambie, E. and Schedl, T. (2007b) Multiple functions and dynamic activation of MPK-1 extracellular signal-regulated kinase signaling in Caenorhabditis elegans germline development. Genetics 177, 2039-2062.   DOI
20 Lee, M. H., Hook, B., Lamont, L. B., Wickens, M. and Kimble, J. (2006) LIP-1 phosphatase controls the extent of germline proliferation in Caenorhabditis elegans. EMBO J. 25, 88-96.   DOI
21 Lino, M. M., Merlo, A. and Boulay, J. L. (2010) Notch signaling in glioblastoma: a developmental drug target? BMC Med. 8, 72.   DOI
22 Liu, J., Sato, C., Cerletti, M. and Wagers, A. (2010) Notch signaling in the regulation of stem cell self-renewal and differentiation. Curr. Top. Dev. Biol. 92, 367-409.   DOI
23 Lomenick, B., Hao, R., Jonai, N., Chin, R. M., Aghajan, M., Warburton, S., Wang, J., Wu, R. P., Gomez, F., Loo, J. A., Wohlschlegel, J. A., Vondriska, T. M., Pelletier, J., Herschman, H. R., Clardy, J., Clarke, C. F. and Huang, J. (2009) Target identification using drug affinity responsive target stability (DARTS). Proc. Natl. Acad. Sci. U.S.A. 106, 21984-21989.   DOI   ScienceOn
24 Lomenick, B., Jung, G., Wohlschlegel, J. A. and Huang, J. (2011) Target identification using drug affinity responsive target stability (DARTS). Curr. Protoc. Chem. Biol. 3, 163-180.
25 Lopez, A. L., 3rd, Chen, J., Joo, H. J., Drake, M., Shidate, M., Kseib, C. and Arur, S. (2013) DAF-2 and ERK couple nutrient availability to meiotic progression during Caenorhabditis elegans oogenesis. Dev. Cell 27, 227-240.   DOI
26 Lublin, A. L. and Link, C. D. (2013) Alzheimer's disease drug discovery: in vivo screening using Caenorhabditis elegans as a model for beta-amyloid peptide-induced toxicity. Drug Discov. Today Technol. 10, e115-119.   DOI
27 Moon, B. S., Jeong, W. J., Park, J., Kim, T. I., Min do, S. and Choi, K. Y. (2014) Role of oncogenic K-Ras in cancer stem cell activation by aberrant Wnt/beta-catenin signaling. J. Natl. Cancer Inst. 106, djt373.   DOI
28 Maine, E. M. and Kimble, J. (1989) Identification of genes that interact with glp-1, a gene required for inductive cell interactions in Caenorhabditis elegans. Development 106, 133-143.
29 Marshall, M. (1995) Interactions between Ras and Raf: key regulatory proteins in cellular transformation. Mol. Reprod. Dev. 42, 493-499.   DOI
30 Miyamoto, S. and Rosenberg, D. W. (2011) Role of Notch signaling in colon homeostasis and carcinogenesis. Cancer Sci. 102, 1938-1942.   DOI   ScienceOn
31 Ferrando, A. A. (2009) The role of NOTCH1 signaling in T-ALL. Hematology Am. Soc. Hematol. Educ. Program, 353-361.
32 Galluzzo, P. and Bocchetta, M. (2011) Notch signaling in lung cancer. Expert Rev. Anticancer Ther. 11, 533-540.   DOI
33 Greenwald, I. (2005) LIN-12/Notch signaling in C. elegans. Worm-Book, 1-16.
34 Hajnal, A. and Berset, T. (2002) The C. elegans MAPK phosphatase LIP-1 is required for the G(2)/M meiotic arrest of developing oocytes. EMBO J. 21, 4317-4326.   DOI
35 Hara, M. and Han, M. (1995) Ras farnesyltransferase inhibitors suppress the phenotype resulting from an activated ras mutation in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 92, 3333-3337.   DOI
36 He, T. C., Sparks, A. B., Rago, C., Hermeking, H., Zawel, L., da Costa, L. T., Morin, P. J., Vogelstein, B. and Kinzler, K. W. (1998) Identification of c-MYC as a target of the APC pathway. Science 281, 1509-1512.   DOI   ScienceOn
37 James, R. G., Conrad, W. H. and Moon, R. T. (2008) Beta-cateninindependent Wnt pathways: signals, core proteins, and effectors. Methods Mol. Biol. 468, 131-144.   DOI   ScienceOn
38 Henderson, S. T., Gao, D., Lambie, E. J. and Kimble, J. (1994) lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans. Development 120, 2913-2924.
39 Holland, J. D., Klaus, A., Garratt, A. N. and Birchmeier, W. (2013) Wnt signaling in stem and cancer stem cells. Curr. Opin. Cell Biol. 25, 254-264.   DOI
40 Hughes, D. P. (2009) How the NOTCH pathway contributes to the ability of osteosarcoma cells to metastasize. Cancer Treat. Res. 152, 479-496.   DOI
41 Katoh, M. (2008) WNT signaling in stem cell biology and regenerative medicine. Curr. Drug Targets 9, 565-570.   DOI   ScienceOn
42 Kidd, A. R., 3rd, Miskowski, J. A., Siegfried, K. R., Sawa, H. and Kimble, J. (2005) A beta-catenin identified by functional rather than sequence criteria and its role in Wnt/MAPK signaling. Cell 121, 761-772.   DOI   ScienceOn
43 Kimble, J. and Crittenden, S. L. (2005) Germline proliferation and its control. WormBook, 1-14.
44 Kimble, J. and Crittenden, S. L. (2007) Controls of germline stem cells, entry into meiosis, and the sperm/oocyte decision in Caenorhabditis elegans. Annu. Rev. Cell Dev. Biol. 23, 405-433.   DOI
45 Lackner, M. R. and Kim, S. K. (1998) Genetic analysis of the Caenorhabditis elegans MAP kinase gene mpk-1. Genetics 150, 103-117.
46 Lam, N., Chesney, M. A. and Kimble, J. (2006) Wnt signaling and CEH-22/tinman/Nkx2.5 specify a stem cell niche in C. elegans. Curr. Biol. 16, 287-295.   DOI   ScienceOn
47 Byrd, D. T., Knobel, K., Affeldt, K., Crittenden, S. L. and Kimble, J. (2014) A DTC niche plexus surrounds the germline stem cell pool in Caenorhabditis elegans. PloS One 9, e88372.   DOI
48 Lamont, L. B., Crittenden, S. L., Bernstein, D., Wickens, M. and Kimble, J. (2004) FBF-1 and FBF-2 regulate the size of the mitotic region in the C. elegans germline. Dev. Cell 7, 697-707.   DOI
49 Blelloch, R. and Kimble, J. (1999) Control of organ shape by a secreted metalloprotease in the nematode Caenorhabditis elegans. Nature 399, 586-590.   DOI
50 Byrd, D. T. and Kimble, J. (2009) Scratching the niche that controls Caenorhabditis elegans germline stem cells. Semin. Cell Dev. Biol. 20, 1107-1113.   DOI   ScienceOn
51 Cha, D. S., Datla, U. S., Hollis, S. E., Kimble, J. and Lee, M. H. (2012) The Ras-ERK MAPK regulatory network controls dedifferentiation in Caenorhabditis elegans germline. Biochim. Biophys. Acta 1823, 1847-1855.   DOI
52 Chen, P. H., Chen, X., Lin, Z., Fang, D. and He, X. (2013) The structural basis of R-spondin recognition by LGR5 and RNF43. Genes Dev. 27, 1345-1350.   DOI
53 Datla, U. S., Scovill, N. C., Brokamp, A. J., Kim, E., Asch, A. S. and Lee, M. H. (2014) Role of PUF-8/PUF protein in stem cell control, sperm-oocyte decision and cell fate reprogramming. J. Cell. Physiol. 229, 1306-1311.   DOI
54 Fan, X., Matsui, W., Khaki, L., Stearns, D., Chun, J., Li, Y. M. and Eberhart, C. G. (2006) Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 66, 7445-7452.   DOI
55 Duncia, J. V., Santella, J. B., 3rd, Higley, C. A., Pitts, W. J., Wityak, J., Frietze, W. E., Rankin, F. W., Sun, J. H., Earl, R. A., Tabaka, A. C., Teleha, C. A., Blom, K. F., Favata, M. F., Manos, E. J., Daulerio, A. J., Stradley, D. A., Horiuchi, K., Copeland, R. A., Scherle, P. A., Trzaskos, J. M., Magolda, R. L., Trainor, G. L., Wexler, R. R., Hobbs, F. W. and Olson, R. E. (1998) MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg. Med. Chem. Lett. 8, 2839-2844.   DOI   ScienceOn
56 Eisenmann, D. M. (2005) Wnt signaling. WormBook 1-17.
57 Ewbank, J. J. and Zugasti, O. (2011) C. elegans: model host and tool for antimicrobial drug discovery. Dis. Model Mech. 4, 300-304.   DOI
58 Favata, M. F., Horiuchi, K. Y., Manos, E. J., Daulerio, A. J., Stradley, D. A., Feeser, W. S., Van Dyk, D. E., Pitts, W. J., Earl, R. A., Hobbs, F., Copeland, R. A., Magolda, R. L., Scherle, P. A. and Trzaskos, J. M. (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273, 18623-18632.   DOI   ScienceOn
59 Feng, Z., Li, W., Ward, A., Piggott, B. J., Larkspur, E. R., Sternberg, P. W. and Xu, X. Z. (2006) A C. elegans model of nicotine-dependent behavior: regulation by TRP-family channels. Cell 127, 621-633.   DOI
60 Allenspach, E. J., Maillard, I., Aster, J. C. and Pear, W. S. (2002) Notch signaling in cancer. Cancer Biol. Ther. 1, 466-476.   DOI
61 Anastassopoulou, C. G., Fuchs, B. B. and Mylonakis, E. (2011) Caenorhabditis elegans-based model systems for antifungal drug discovery. Curr. Pharm. Des. 17, 1225-1233.   DOI
62 Artavanis-Tsakonas, S., Rand, M. D. and Lake, R. J. (1999) Notch signaling: cell fate control and signal integration in development. Science 284, 770-776.   DOI   ScienceOn
63 Avila, J. L. and Kissil, J. L. (2013) Notch signaling in pancreatic cancer: oncogene or tumor suppressor? Trends Mol. Med. 19, 320-327.   DOI
64 Abel, E. V., Kim, E. J., Wu, J., Hynes, M., Bednar, F., Proctor, E., Wang, L., Dziubinski, M. L. and Simeone, D. M. (2014). The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer. PLoS One 9, e91983.   DOI
65 Ahn, D., Cha, D. S., Lee, E. B., Kim, B. J., Lee, S. Y., Jeon, H., Ahn, M. S., Lim, H. W., Lee, H. Y. and Kim, D. K. (2013) The longevity properties of 1,2,3,4,6-Penta-O-Galloyl-beta-D-Glucose from Curcuma longa in Caenorhabditis elegans. Biomol. Ther. 21, 442-446.   DOI
66 Benson, J. A., Cummings, E. E., O'Reilly, L. P., Lee, M. H. and Pak, S. C. (2014) A high-content assay for identifying small molecules that reprogram C. elegans germ cell fate. Methods 68, 529-535.   DOI
67 Bae, Y. K., Sung, J. Y., Kim, Y. N., Kim, S., Hong, K. M., Kim, H. T., Choi, M. S., Kwon, J. Y. and Shim, J. (2012) An in vivo C. elegans model system for screening EGFR-inhibiting anti-cancer drugs. PLoS One 7, e42441.   DOI
68 Bao, B., Wang, Z., Ali, S., Kong, D., Li, Y., Ahmad, A., Banerjee, S., Azmi, A. S., Miele, L. and Sarkar, F. H. (2011) Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett. 307, 26-36.   DOI   ScienceOn
69 Beitel, G. J., Clark, S. G. and Horvitz, H. R. (1990) Caenorhabditis elegans ras gene let-60 acts as a switch in the pathway of vulval induction. Nature 348, 503-509.   DOI
70 Berry, L. W., Westlund, B. and Schedl, T. (1997) Germ-line tumor formation caused by activation of glp-1, a Caenorhabditis elegans member of the Notch family of receptors. Development 124, 925-936.
71 Berset, T., Hoier, E. F., Battu, G., Canevascini, S. and Hajnal, A. (2001) Notch inhibition of RAS signaling through MAP kinase phosphatase LIP-1 during C. elegans vulval development. Science 291, 1055-1058.   DOI
72 Birchmeier, W. (2011) Stem cells: Orphan receptors find a home. Nature 476, 287-288.   DOI   ScienceOn
73 Blelloch, R., Anna-Arriola, S. S., Gao, D., Li, Y., Hodgkin, J. and Kimble, J. (1999) The gon-1 gene is required for gonadal morphogenesis in Caenorhabditis elegans. Dev. Biol. 216, 382-393.   DOI
74 Wang, D., Huang, B., Zhang, S., Yu, X., Wu, W. and Wang, X. (2013) Structural basis for R-spondin recognition by LGR4/5/6 receptors. Genes Dev. 27, 1339-1344.   DOI
75 Zhao, Y., Bjorbaek, C. and Moller, D. E. (1996) Regulation and interaction of pp90(rsk) isoforms with mitogen-activated protein kinases. J. Biol. Chem. 271, 29773-29779.   DOI
76 Wend, P., Holland, J. D., Ziebold, U. and Birchmeier, W. (2010) Wnt signaling in stem and cancer stem cells. Semin. Cell Dev. Biol. 21, 855-863.   DOI   ScienceOn
77 Whelan, J. T., Hollis, S. E., Cha, D. S., Asch, A. S. and Lee, M. H. (2012) Post-transcriptional regulation of the Ras-ERK/MAPK signaling pathway. J. Cell. Physiol. 227, 1235-1241.   DOI
78 Yoo, A. S., Bais, C. and Greenwald, I. (2004) Crosstalk between the EGFR and LIN-12/Notch pathways in C. elegans vulval development. Science 303, 663-666.   DOI
79 Schouest, K. R., Kurasawa, Y., Furuta, T., Hisamoto, N., Matsumoto, K. and Schumacher, J. M. (2009) The germinal center kinase GCK-1 is a negative regulator of MAP kinase activation and apoptosis in the C. elegans germline. PLoS One 4, e7450.   DOI
80 Schulze, W. X., Deng, L. and Mann, M. (2005) Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol. Syst. Biol. 1, 2005 0008.
81 Sellings, L., Pereira, S., Qian, C., Dixon-McDougall, T., Nowak, C., Zhao, B., Tyndale, R. F. and van der Kooy, D. (2013) Nicotine-motivated behavior in Caenorhabditis elegans requires the nicotinic acetylcholine receptor subunits acr-5 and acr-15. Eur. J. Neurosci. 37, 743-756.   DOI
82 Siegfried, K. R. and Kimble, J. (2002) POP-1 controls axis formation during early gonadogenesis in C. elegans. Development 129, 443-453.
83 Sundaram, M. V. (2006) RTK/Ras/MAPK signaling. WormBook, 1-19.
84 Smith, M. A., Jr., Zhang, Y., Polli, J. R., Wu, H., Zhang, B., Xiao, P., Farwell, M. A. and Pan, X. (2013) Impacts of chronic low-level nicotine exposure on Caenorhabditis elegans reproduction: identification of novel gene targets. Reprod. Toxicol. 40, 69-75.   DOI
85 Squiban, B. and Kurz, C. L. (2011) C. elegans: an all in one model for antimicrobial drug discovery. Curr. Drug Targets 12, 967-977.   DOI
86 Sun, W., Gaykalova, D. A., Ochs, M. F., Mambo, E., Arnaoutakis, D., Liu, Y., Loyo, M., Agrawal, N., Howard, J., Li, R., Ahn, S., Fertig, E., Sidransky, D., Houghton, J., Buddavarapu, K., Sanford, T., Choudhary, A., Darden, W., Adai, A., Latham, G., Bishop, J., Sharma, R., Westra, W. H., Hennessey, P., Chung, C. H. and Califano, J. A. (2014) Activation of the NOTCH pathway in head and neck cancer. Cancer Res. 74, 1091-1104.   DOI   ScienceOn
87 Taki, F. A., Pan, X. and Zhang, B. (2014) Chronic nicotine exposure systemically alters microRNA expression profiles during postembryonic stages in Caenorhabditis elegans. J. Cell. Physiol. 229, 79-89.
88 Tamura, Y., Simizu, S. and Osada, H. (2004) The phosphorylation status and anti-apoptotic activity of Bcl-2 are regulated by ERK and protein phosphatase 2A on the mitochondria. FEBS Lett. 569, 249-255.   DOI   ScienceOn
89 Tetsu, O. and McCormick, F. (1999) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422-426.   DOI   ScienceOn
90 Tilmann, C. and Kimble, J. (2005) Cyclin D regulation of a sexually dimorphic asymmetric cell division. Dev. Cell 9, 489-499.   DOI
91 Kershner, A. M., Shin, H., Hansen, T. J. and Kimble, J. (2014) Discovery of two GLP-1/Notch target genes that account for the role of GLP-1/Notch signaling in stem cell maintenance. Proc. Natl. Acad. Sci. U.S.A. 111, 3739-3744.   DOI
92 Chamorro, M. N., Schwartz, D. R., Vonica, A., Brivanlou, A. H., Cho, K. R. and Varmus, H. E. (2005) FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development. EMBO J. 24, 73-84.   DOI
93 Eckmann, C. R., Kraemer, B., Wickens, M. and Kimble, J. (2002) GLD-3, a bicaudal-C homolog that inhibits FBF to control germline sex determination in C. elegans. Dev. Cell 3, 697-710.   DOI
94 Austin, J. and Kimble, J. (1987) glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans. Cell 51, 589-599.   DOI   ScienceOn
95 Pennica, D., Swanson, T. A., Welsh, J. W., Roy, M. A., Lawrence, D. A., Lee, J., Brush, J., Taneyhill, L. A., Deuel, B., Lew, M., Watanabe, C., Cohen, R. L., Melhem, M. F., Finley, G. G., Quirke, P., Goddard, A. D., Hillan, K. J., Gurney, A. L., Botstein, D. and Levine, A. J. (1998) WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc. Natl. Acad. Sci. U.S.A. 95, 14717-14722.   DOI
96 Lee, M. H., Hook, B., Pan, G., Kershner, A. M., Merritt, C., Seydoux, G., Thomson, J. A., Wickens, M. and Kimble, J. (2007a) Conserved regulation of MAP kinase expression by PUF RNA-binding proteins. PLoS Genet. 3, e233.   DOI