Wei Du, Ph.D.

Rb tumor suppressor, control of cell proliferation and differentiation

Research Summary

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.

Selected Papers

Li, B., Gordon, GM., Du, CH., Xu, J., and Du, W. (2010) Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell. 17, 469–480. NIHMSID #196476.

Li, B, Wang, CZ, He, TC, Yuan, CS, Du, W. (2010) Antioxidants potentiate American ginseng-induced apoptosis in colorectal cancer cells. Cancer Lett. 289, 62-70. [Epub 2009 Aug 27]. NIHMSID: NIHMS141750.

Steele, L., Sukhanova, MJ., Xu, J., Gordon, GM., Huang, Y, Yu, L., and Du, W. (2009) Rhinoceros and Retinoblastoma family protein regulate Delta expression during photoreceptor R8 determination. Dev Biol. 335, 228–236. NIHMSID: NIHMS144795.

Tanaka-Matakatsu, M., Xu, J., Cheng, L., and Du, W. (2009) Regulation of apoptosis of rbf mutant cells during Drosophila development. Dev Biol. 326, 347-56. NIHMSID # 84081.

Sukhanova, MJ and Du, W. (2008) Control of Cell Cycle Entry and Exiting from the Second Mitotic Wave in the Drosophila Developing Eye. BMC Developmental Biology. 8, 7. PMCID: PMC2267170.

Deb,DK, Matakatsu, MT, Jones, L., Richardson, HE, and Du, W. (2008) Wingless signaling directly regulates cyclin E expression in proliferating embryonic PNS precursor cells. Mechanisms of Dev. 125, 857-64. NIHMSID # 71787.

Matakatsu, MT, and Du, W. (2008) Direct control of proneural gene atonal by retinal determination factors during Drosophila eye development. Dev Biol. 313, 787-801. PMCID: PMC2231519.

Sukhanova, M. Deb, D.K., Gordon, G.M., Matakatsu, MT, and Du, W. (2007) Proneural bHLH proteins and EGFR signaling coordinately regulate cell type specification and cdk inhibitor expression in Drosophila. MCB, 27, 2987-96. PMCID: PMC1899942.

Matakatsu, MT, Thomas, BJ, and Du, W. (2007) Mutation of the Apc1 homologue shattered disrupts normal eye development by disrupting G1 cell cycle arrest and progression through mitosis. Dev Biol. 309, 222-235. (Epub 2007 Jul 14). PMCID: PMC2080841.

Pogoriler J., Millen, K., Utset, M., and Du, W. (2006) Loss of cyclin D1 impairs cerebellar development and suppresses medulloblastoma formation. Development, 133, 3929-3937. PMCID: PMC1868525.

Du, W. and Pogoriler, J (2006) Retinoblastoma Family Genes. Oncogene, 25, 5190-5200. PMCID: PMC1899835.

Pogoriler, J and Du, W. (2004) Chk1 activation and the nuclear/cytoplasmic ratio.  Developmental Cell, 7, 147-148.
Duman-Scheel, M., Johnston, L., and Du, W. (2004) Repression of dMyc expression by Wingless promotes RBF-induced G1 arrest in the Presumptive Drosophila Wing Margin.  PNAS, 101, 3857–3862.

Weng, L., Zhu, C., Xu, J. and Du, W. (2003) Critical role of active repression by E2F and Rb proteins in endoreplication during Drosophila development.  EMBO J., 22, 3865-3875.

Xu, J. and Du, W. (2003) Drosophila chk2 plays an important role in a mitotic checkpoint in syncytial embryos.  FEBS letter, 545, 209-212.

Duman-Scheel, M., Weng, L., Xin, S., and Du, W. (2002) Hedgehog signaling controls cell proliferation and growth through upregulation of Cyclin D and Cyclin E.  Nature, 417, 299-304.

Xin, S., Weng, L., Xu, J., and Du, W. (2002) The role of RBF in developmentally regulated cell proliferation in the eye disc and in Cyclin D/Cdk4 induced cellular growth.  Development. 129, 1345-1356.

Xu, J., S. Xin, and W. Du. (2001). Drosophila Chk2 is required for DNA damage-mediated cell cycle arrest and apoptosis. FEBS Letters 508, 394-398.

Du, W. (2000) Suppression of the rbf null mutants by a de2f1 allele that lacks transactivation domain. Development.  127, 367-379.