DF/HCC Program Affiliation

Leukemia

Research Abstract

Our research focuses on signaling pathways triggered by inositol phospholipid PtdIns(3,4,5)P3, which has been implicated in various cellular processes such as proliferation, growth, apoptosis, polarity, chemotaxis and cytoskeletal rearrangement. PtdIns(3,4,5)P3 exerts its function by mediating protein translocation via binding to their pleckstrin homolog (PH)-domains. Membrane translocation of PH-domains was previously thought to be dependent solely upon concentrations of PtdIns(3,4,5)P3 in the membrane which is regulated by PI3K and PTEN. Recently, we discovered that two intracellular inositol phosphates InsP7 and Ins(1,3,4,5)P4 compete with PtdIns(3,4,5)P3 for binding to the PH domains, and thereby attenuate their membrane translocation. This result provides another level of regulation for PH domain translocation, namely relative levels of InsP7 and PtdIns(3,4,5)P3. Our lab will continue to elucidate the molecular mechanism and the physiological consequence of the inositol phosphate-mediated suppression of PtdIns(3,4,5)P3 signaling in a variety of cellular processes. #p Our lab is also interested in the cellular pathways contributing to the anti-cancer activity of all-trans retinoic acid (ATRA) in the promyelocytic leukemia (PML). Retinoic acid signaling is mediated by nuclear retinoic acid receptor (RAR), while the downstream pathways are poorly understood. We are conducting a genome wide RNAi screen in a PML cell line to identify downstream factors that are required for retinoic acid receptor signaling.

Publications

• Luo HR, Hattori H, Hossain MA, Hester L, Huang Y, Lee-Kwon W, Donowitz M, Nagata E, Snyder SH.Akt as a mediator of cell death.Proc Natl Acad Sci U S A 2003 Sep 30;100(20):11712-7.
  14504398
• Luo HR, Huang YE, Chen JC, Saiardi A, Iijima M, Ye K, Huang Y, Nagata E, Devreotes P, Snyder SH.Inositol pyrophosphates mediate chemotaxis in Dictyostelium via pleckstrin homology domain-PtdIns(3,4,5)P3 interactions.Cell 2003 Sep 5;114(5):559-72.
  13678580
• Luo HR, Saiardi A, Yu H, Nagata E, Ye K, Snyder SH.Inositol pyrophosphates are required for DNA hyperrecombination in protein kinase c1 mutant yeast.Biochemistry 2002 Feb 26;41(8):2509-15.
  11851397
• Luo HR, Saiardi A, Nagata E, Ye K, Yu H, Jung TS, Luo X, Jain S, Sawa A, Snyder SH.GRAB: a physiologic guanine nucleotide exchange factor for Rab3A, which interacts with inositol hexakisphosphate kinase.Neuron 2001 Aug 16;31(3):439-51.
  11516400