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Wei Du

Professor
wei@uchicago.edu
Research Summary
Rb Tumor Suppressor, Control of Cell Proliferation and Differentiation 1) Novel approaches to target the loss of tumor suppressors in cancers The success of cancer therapies generally depend on their ability to target certain unique requirements of the cancer cells that are distinct from those of the normal cells. Current targeted cancer therapies at different stages of development mostly focus on inhibiting the deregulated oncogenic pathways kinases in cancers. In addition to deregulated oncogenic activation, cancer cells also often have inactivation of tumor suppressors. However such knowledge has yet to be exploited to develop targeted cancer therapies due to a lack of approaches to restore the lost tumor suppressor function in all the cancer cells and a lack of knowledge about the genes that are synthetic lethal with the lost tumor suppressors. While it is possible to carry out genome-wide RNAi screen to identify genes that are synthetic lethal with Rb using cell culture assays, such screen will depend largely on the particular culture conditions and may or may not reflect the in vivo situations. Rb is a tumor suppressor that is often lost in cancers. Because the Rb/E2F pathway is highly conserved between flies and mammalian systems, we hypothesize that genes that are synthetic lethal with loss of Rb will be conserved between the two systems as well. In a genetic screen for genes that can modulate the consequences of Rb loss, we found that mutation of gig, the Drosophila TSC2 homolog, show synergistically increased cell death with loss of Rb. Interestingly, knockdown of TSC2 in human cancer cells blocks cancer cell growth and induced cell death dependent on the Rb status, suggesting that TSC2 can potentially be used to specifically target Rb mutant cancers. Research in the lab include further characterization of the mechanisms of synergistic cell death induction, identification of genes/pathways/chemical inhibitors that can enhance the specific cell death induction by TSC2 knockdown, developing assays to screen for small molecule inhibitors of TSC2 function, and carry out additional genetic screen to identify additional potential targets. 2) Molecular mechanisms that coordinate the control of cell proliferation and differentiation during normal development We use the Drosophila developing eye as a model system to elucidate mechanisms by which developmental mechanisms coordinate cell proliferation and differentiation. In third instar eye discs, the morphogenetic furrow (MF), which is marked by an indentation in the eye disc, moves from posterior of the eye disc to the anterior. Cells anterior to the MF are asynchronously proliferating, which become cell cycle arrest in G1 in the MF. Photoreceptor differentiation initiates in the MF and the first photoreceptor determined is R8. R8 photoreceptor differentiation is controlled by the Atonal (Ato), a bHLH protein initially expressed in the MF and then restricted to the future R8 cells. Therefore one project in the lab is to elucidate the regulation of Ato expression, which is regulated by retinal determination genes and developmental signaling pathways. Cells in the MF and the differentiating photoreceptor clusters are arrested in G1. immediately posterior to the MF, cells not in the photoreceptor clusters undergo a synchronous round of cell cycle called second mitotic wave (SMW). Notch and EGFR signaling plays critical roles in controlling photoreceptor differentiation or cell proliferation. We are investigating the molecular mechanisms by which these developmental signaling pathways coordinate cell proliferation and differentiation.
Keywords
Retinoblastoma Protein, E2F Transcription Factors, Cell proliferation and cell death, Drosophila, retina development
Education
  • Fudan University, Shanghai, China, B.S. Biochemistry
  • Harvard University, Cambridge, MA, Ph.D. Biochemistry and Molecular Biology
  • Harvard Medical School/MGH Cancer Center, Boston, MA, postdoc Molecular Oncology
Biosciences Graduate Program Association
Awards & Honors
  • 1998 - 2000 Sydney Kimmel Scholar
  • 2003 - 2008 Leukemia & Lymphoma Society Scholar
  • 2006 - 2008 Cancer Research Foundation Fletcher Scholar
Publications

  1. Reversal of hyperactive Wnt signaling-dependent adipocyte defects by peptide boronic acids. Proc Natl Acad Sci U S A. 2017 09 05; 114(36):E7469-E7478. View in: PubMed

  2. Loss of histone deacetylase HDAC1 induces cell death in Drosophila epithelial cells through JNK and Hippo signaling. Mech Dev. 2016 08; 141:4-13. View in: PubMed

  3. ESCRT-0 complex modulates Rbf-mutant cell survival by regulating Rhomboid endosomal trafficking and EGFR signaling. J Cell Sci. 2016 05 15; 129(10):2075-84. View in: PubMed

  4. Red ginseng and cancer treatment. Chin J Nat Med. 2016 Jan; 14(1):7-16. View in: PubMed

  5. Groucho restricts rhomboid expression and couples EGFR activation with R8 selection during Drosophila photoreceptor differentiation. Dev Biol. 2015 Nov 15; 407(2):246-55. View in: PubMed

  6. American ginseng significantly reduced the progression of high-fat-diet-enhanced colon carcinogenesis in Apc (Min/+) mice. J Ginseng Res. 2015 Jul; 39(3):230-7. View in: PubMed

  7. TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol. J Pharmacol Sci. 2015 Jan; 127(1):83-91. View in: PubMed

  8. American ginseng attenuates azoxymethane/dextran sodium sulfate-induced colon carcinogenesis in mice. J Ginseng Res. 2015 Jan; 39(1):14-21. View in: PubMed

  9. The homeodomain of Eyeless regulates cell growth and antagonizes the paired domain-dependent retinal differentiation function. Protein Cell. 2015 Jan; 6(1):68-78. View in: PubMed

  10. Chemopreventive effects of oplopantriol A, a novel compound isolated from Oplopanax horridus, on colorectal cancer. Nutrients. 2014 Jul 18; 6(7):2668-80. View in: PubMed

  11. Daughterless homodimer synergizes with Eyeless to induce Atonal expression and retinal neuron differentiation. Dev Biol. 2014 Aug 15; 392(2):256-65. View in: PubMed

  12. Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities. PLoS Genet. 2014 May; 10(5):e1004357. View in: PubMed

  13. Anticancer compound Oplopantriol A kills cancer cells through inducing ER stress and BH3 proteins Bim and Noxa. Cell Death Dis. 2014 Apr 24; 5:e1190. View in: PubMed

  14. A nutritional conditional lethal mutant due to pyridoxine 5'-phosphate oxidase deficiency in Drosophila melanogaster. G3 (Bethesda). 2014 Apr 16; 4(6):1147-54. View in: PubMed

  15. Mutation of the retinoblastoma tumor suppressor gene sensitizes cancers to mitotic inhibitor induced cell death. Am J Cancer Res. 2014; 4(1):42-52. View in: PubMed

  16. Panax notoginseng attenuates experimental colitis in the azoxymethane/dextran sulfate sodium mouse model. Phytother Res. 2014 Jun; 28(6):892-8. View in: PubMed

  17. Identification of potential anticancer compounds from Oplopanax horridus. Phytomedicine. 2013 Aug 15; 20(11):999-1006. View in: PubMed

  18. Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells. Int J Oncol. 2013 Jul; 43(1):289-96. View in: PubMed

  19. Deregulated G1-S control and energy stress contribute to the synthetic-lethal interactions between inactivation of RB and TSC1 or TSC2. J Cell Sci. 2013 May 01; 126(Pt 9):2004-13. View in: PubMed

  20. Compound K, a Ginsenoside Metabolite, Inhibits Colon Cancer Growth via Multiple Pathways Including p53-p21 Interactions. Int J Mol Sci. 2013 Jan 31; 14(2):2980-95. View in: PubMed

  21. Paraptosis and NF-?B activation are associated with protopanaxadiol-induced cancer chemoprevention. BMC Complement Altern Med. 2013 Jan 03; 13:2. View in: PubMed

  22. Functional inactivation of Rb sensitizes cancer cells to TSC2 inactivation induced cell death. Cancer Lett. 2013 Jan 01; 328(1):36-43. View in: PubMed

  23. The antitumor natural compound falcarindiol promotes cancer cell death by inducing endoplasmic reticulum stress. Cell Death Dis. 2012 Aug 23; 3:e376. View in: PubMed

  24. The synergistic apoptotic interaction of panaxadiol and epigallocatechin gallate in human colorectal cancer cells. Phytother Res. 2013 Feb; 27(2):272-7. View in: PubMed

  25. Caspase-mediated pro-apoptotic interaction of panaxadiol and irinotecan in human colorectal cancer cells. J Pharm Pharmacol. 2012 May; 64(5):727-34. View in: PubMed

  26. Conserved RB functions in development and tumor suppression. Protein Cell. 2011 Nov; 2(11):864-78. View in: PubMed

  27. RBF and Rno promote photoreceptor differentiation onset through modulating EGFR signaling in the Drosophila developing eye. Dev Biol. 2011 Nov 15; 359(2):190-8. View in: PubMed

  28. Targeting Rb inactivation in cancers by synthetic lethality. Am J Cancer Res. 2011 Jun 30; 1(6):773-86. View in: PubMed

  29. Ginsenoside Rh2 induces apoptosis and paraptosis-like cell death in colorectal cancer cells through activation of p53. Cancer Lett. 2011 Feb 28; 301(2):185-92. View in: PubMed

  30. Sonic hedgehog signaling induces vascular smooth muscle cell proliferation via induction of the G1 cyclin-retinoblastoma axis. Arterioscler Thromb Vasc Biol. 2010 Sep; 30(9):1787-94. View in: PubMed

  31. Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell. 2010 May 18; 17(5):469-80. View in: PubMed

  32. Retinoblastoma family protein promotes normal R8-photoreceptor differentiation in the absence of rhinoceros by inhibiting dE2F1 activity. Dev Biol. 2009 Nov 01; 335(1):228-36. View in: PubMed

  33. American ginseng berry enhances chemopreventive effect of 5-FU on human colorectal cancer cells. Oncol Rep. 2009 Oct; 22(4):943-52. View in: PubMed

  34. In vitro and in vivo anticancer effects of American ginseng berry: exploring representative compounds. Biol Pharm Bull. 2009 Sep; 32(9):1552-8. View in: PubMed

  35. Antioxidants potentiate American ginseng-induced killing of colorectal cancer cells. Cancer Lett. 2010 Mar 01; 289(1):62-70. View in: PubMed

  36. The rb pathway and cancer therapeutics. Curr Drug Targets. 2009 Jul; 10(7):581-9. View in: PubMed

  37. Regulation of apoptosis of rbf mutant cells during Drosophila development. Dev Biol. 2009 Feb 15; 326(2):347-56. View in: PubMed

  38. Antiproliferative effects of different plant parts of Panax notoginseng on SW480 human colorectal cancer cells. Phytother Res. 2009 Jan; 23(1):6-13. View in: PubMed

  39. Chemopreventive effects of heat-processed Panax quinquefolius root on human breast cancer cells. Anticancer Res. 2008 Sep-Oct; 28(5A):2545-51. View in: PubMed

  40. Wingless signaling directly regulates cyclin E expression in proliferating embryonic PNS precursor cells. Mech Dev. 2008 Sep-Oct; 125(9-10):857-64. View in: PubMed

  41. The evolution of courtship behaviors through the origination of a new gene in Drosophila. Proc Natl Acad Sci U S A. 2008 May 27; 105(21):7478-83. View in: PubMed

  42. Characterization of gene expression regulated by American ginseng and ginsenoside Rg3 in human colorectal cancer cells. Int J Oncol. 2008 May; 32(5):975-83. View in: PubMed

  43. Control of cell cycle entry and exiting from the second mitotic wave in the Drosophila developing eye. BMC Dev Biol. 2008 Jan 24; 8:7. View in: PubMed

  44. Direct control of the proneural gene atonal by retinal determination factors during Drosophila eye development. Dev Biol. 2008 Jan 15; 313(2):787-801. View in: PubMed

  45. Chemopreventive effects of Panax notoginseng and its major constituents on SW480 human colorectal cancer cells. Int J Oncol. 2007 Nov; 31(5):1149-56. View in: PubMed

  46. Mutation of the Apc1 homologue shattered disrupts normal eye development by disrupting G1 cell cycle arrest and progression through mitosis. Dev Biol. 2007 Sep 15; 309(2):222-35. View in: PubMed

  47. Proneural basic helix-loop-helix proteins and epidermal growth factor receptor signaling coordinately regulate cell type specification and cdk inhibitor expression during development. Mol Cell Biol. 2007 Apr; 27(8):2987-96. View in: PubMed

  48. Loss of cyclin D1 impairs cerebellar development and suppresses medulloblastoma formation. Development. 2006 Oct; 133(19):3929-37. View in: PubMed

  49. Retinoblastoma family genes. Oncogene. 2006 Aug 28; 25(38):5190-200. View in: PubMed

  50. Cyclopamine increases the cytotoxic effects of paclitaxel and radiation but not cisplatin and gemcitabine in Hedgehog expressing pancreatic cancer cells. Cancer Chemother Pharmacol. 2006 Dec; 58(6):765-70. View in: PubMed

  51. Detecting novel low-abundant transcripts in Drosophila. RNA. 2005 Jun; 11(6):939-46. View in: PubMed

  52. Chk1 activation and the nuclear/cytoplasmic ratio. Dev Cell. 2004 Aug; 7(2):147-8. View in: PubMed

  53. Repression of dMyc expression by Wingless promotes Rbf-induced G1 arrest in the presumptive Drosophila wing margin. Proc Natl Acad Sci U S A. 2004 Mar 16; 101(11):3857-62. View in: PubMed

  54. Endocycle and E2F-dependent transcriptional activation and repression. Cell Cycle. 2003 Nov-Dec; 2(6):515-6. View in: PubMed

  55. Critical role of active repression by E2F and Rb proteins in endoreplication during Drosophila development. EMBO J. 2003 Aug 01; 22(15):3865-75. View in: PubMed

  56. Drosophila chk2 plays an important role in a mitotic checkpoint in syncytial embryos. FEBS Lett. 2003 Jun 19; 545(2-3):209-12. View in: PubMed

  57. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature. 2002 May 16; 417(6886):299-304. View in: PubMed

  58. The role of RBF in developmentally regulated cell proliferation in the eye disc and in Cyclin D/Cdk4 induced cellular growth. Development. 2002 Mar; 129(6):1345-56. View in: PubMed

  59. Drosophila Chk2 is required for DNA damage-mediated cell cycle arrest and apoptosis. FEBS Lett. 2001 Nov 23; 508(3):394-8. View in: PubMed

  60. DNA replication control through interaction of E2F-RB and the origin recognition complex. Nat Cell Biol. 2001 Mar; 3(3):289-95. View in: PubMed

  61. Drosophila Cdk4 is required for normal growth and is dispensable for cell cycle progression. EMBO J. 2000 Sep 01; 19(17):4533-42. View in: PubMed

  62. Suppression of the rbf null mutants by a de2f1 allele that lacks transactivation domain. Development. 2000 Jan; 127(2):367-79. View in: PubMed

  63. The role of RBF in the introduction of G1 regulation during Drosophila embryogenesis. EMBO J. 1999 Feb 15; 18(4):916-25. View in: PubMed

  64. RBF, a novel RB-related gene that regulates E2F activity and interacts with cyclin E in Drosophila. Genes Dev. 1996 May 15; 10(10):1206-18. View in: PubMed

  65. Ectopic expression of dE2F and dDP induces cell proliferation and death in the Drosophila eye. EMBO J. 1996 Jul 15; 15(14):3684-92. View in: PubMed

  66. Requirements for dE2F function in proliferating cells and in post-mitotic differentiating cells. EMBO J. 1996 Jul 15; 15(14):3676-83. View in: PubMed

  67. Mechanisms of transcriptional synergism between distinct virus-inducible enhancer elements. Cell. 1993 Sep 10; 74(5):887-98. View in: PubMed

  68. The high mobility group protein HMG I(Y) can stimulate or inhibit DNA binding of distinct transcription factor ATF-2 isoforms. Proc Natl Acad Sci U S A. 1994 Nov 22; 91(24):11318-22. View in: PubMed

  69. The high mobility group protein HMG I(Y) is an essential structural component of a virus-inducible enhancer complex. Cold Spring Harb Symp Quant Biol. 1993; 58:73-81. View in: PubMed

  70. An ATF/CREB binding site is required for virus induction of the human interferon beta gene [corrected]. Proc Natl Acad Sci U S A. 1992 Mar 15; 89(6):2150-4. View in: PubMed
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