Stem cells have the unique property of producing specialized cells and regenerating damaged tissues. After a stem cell divides, one descendent remains a stem cell, while the other becomes a specialized cell. Understanding how an offspring chooses between stem or specialized cell fates holds potential for breakthroughs in cancer treatment. Human tumors have - cancer stem cells - that survive chemotherapy and then establish new, more aggressive tumors.
Stem cell numbers in mammals are regulated by JAK and STAT proteins. In normal cells, their activities are regulated to relay a signal from the outside of a cell to its interior. Continuous activity of JAKs and STATs causes human cancers. Reducing the activity of STAT proteins significantly impairs the survival of human cancer cells. These results indicate that JAKs and STATs are good candidates for therapeutic intervention.
The normal and cancer-causing activities of JAKs and STATs are not well understood. JAK and STAT genes exist in very similar forms in the fruit fly, Drosophila, which is an excellent genetic organism that has been used successfully to study genes involved in human diseases. Persistent activation of JAK and STAT proteins in the fly eye and testis leads to dramatic overgrowths that consist of stem cells resembling human tumors. Furthermore, when these proteins do not work, stem cells are lost. We have identified genes that JAKs and STATs turn on: cyclin E, which regulates mitosis; dmyc, which regulates size; and chinmo, which regulates stem-ness. We will address whether these proteins increase stem cell division by controlling the level of Cyclin E. We will ask if JAKs and STATs increase stem cell size by increasing dMyc. We will address how Chinmo allows a stem cell offspring to choose a stem or differentiated fate. Our study should result in better therapeutics for human patients.
Kim BH, Jee JG, Yin CH, Sandoval C, Jayabose S, Kitamura D, Bach EA, Baeg GH. NSC114792, a novel small molecule identified through structure-based computational database screening, selectively inhibits JAK3. Mol Cancer. 2010 Feb 11;9(1):36.
Kim BH, Oh SR, Yin CH, Lee S, Kim EA, Kim MS, Sandoval C, Jayabose S, Bach EA, Lee HK, Baeg GH. MS-1020 is a novel small molecule that selectively inhibits JAK3 activity. Br J Haematol. 2010 Jan;148(1):132-43.
Flaherty MS, Zavadil J, Ekas LA, Bach EA. Genome-wide expression profiling in the Drosophila eye reveals unexpected repression of notch signaling by the JAK/STAT pathway. Dev Dyn. 2009 Jun 4.
Kim BH, Yin CH, Guo Q, Bach EA, Lee H, Sandoval C, Jayabose S, Ulaczyk-Lesanko A, Hall DG, Baeg GH. A small-molecule compound identified through a cell-based screening inhibits JAK/STAT pathway signaling in human cancer cells. Mol Cancer Ther. 2008 Sep;7(9):2672-80.
Ayala-Camargo A, Ekas LA, Flaherty MS, Baeg GH, Bach EA. The JAK/STAT pathway regulates proximo-distal patterning in Drosophila. Dev Dyn. 2007 Oct;236(10):2721-30.
Bach EA, Ekas LA, Ayala-Camargo A, Flaherty MS, Lee H, Perrimon N, Baeg GH. GFP reporters detect the activation of the Drosophila JAK/STAT pathway in vivo. Gene Expr Patterns. 2007 Jan;7(3):323-31.
Ekas LA, Baeg GH, Flaherty MS, Ayala-Camargo A, Bach EA. JAK/STAT signaling promotes regional specification by negatively regulating wingless expression in Drosophila. Development. 2006 Dec;133(23):4721-9.
Arbouzova NI, Bach EA, Zeidler MP. Ken & Barbie selectively regulates the expression of a subset of Jak/STAT pathway target genes. Curr Biol. 2006 Jan 10;16(1):80-8.
Read RD, Bach EA, Cagan RL. Drosophila C-terminal Src kinase negatively regulates organ growth and cell proliferation through inhibition of the Src, Jun N-terminal kinase, and STAT pathways. Mol Cell Biol. 2004 Aug;24(15):6676-89.
Bach EA, Vincent S, Zeidler MP, Perrimon N. A sensitized genetic screen to identify novel regulators and components of the Drosophila janus kinase/signal transducer and activator of transcription pathway. Genetics. 2003 Nov;165(3):1149-66.
Ghiglione C, Bach EA, Paraiso Y, Carraway KL 3rd, Noselli S, Perrimon N. Mechanism of activation of the Drosophila EGF Receptor by the TGFalpha ligand Gurken during oogenesis. Development. 2002 Jan;129(1):175-86.
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Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, Kaplan DH, Riley JK, Greenlund AC, Campbell D, Carver-Moore K, DuBois RN, Clark R, Aguet M, Schreiber RD. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell. 1996 Feb 9;84(3):431-42.
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