RESEARCH DESCRIPTION
1. Identifiation and functional studies of murine or human HPS genes
Hermansky-Pudlak syndrome (HPS) is a heterogeneous recessive disorder characterized by oculocutaneous albinism, bleeding tendency and ceroid deposition by affecting the biogenesis of several lysosome-related organelles such as melanosomes, platelet dense granules. During the past three decades, Dr. Richard T. Swank's laboratory have identified at least 16 mouse Hermansky-Pudlak syndrome (HPS) mutants (reviewed by Swank RT, et al. Pigment Cell Res, 1998). Through positional candidate cloning, the first human HPS gene, HPS1, was identified in 1996. This prompted the identification of the first murine HPS gene, Hps1/ep, in 1997 and the cloning of other 15 HPS genes in mouse or human thereafter (reviewed by Li W, et al. BioEssays, 2004). Data integration of all these HPS genes is deposited in the Hermansky-Pudlak Syndrome Database (Li W, et al. Hum Mutat,2006).
Currently, the 16 cloned HPS genes fall
into two classes. The first class, presented both in lower and higher
eukaryotic species, includes genes well known to encode components or
regulators of intracellular vesicle trafficking (reviewed by Swank RT, et al. Pigment Cell Res, 2000), such as subunits of
AP-3 adaptor complex, Rab27a, VPS33a, and Rab geranylgeranyl transferase alpha
subunit (Detter JC, et al. PNAS, 2000; Li W, et al. Mol Genet Metab, 2000; Zhang Q, et al. Br J Heamatol, 2002). This makes
perfect sense of the organellar abnormalities in HPS patients and
enters into knowledge of the molecular and cellular mechanism of HPS.
The second class(first proposed in Zhang Q, et al. Hum Mol Genet, 2002), presented only in higher eukaryotic organisms, is
composed of at least ten novel HPS genes. This category is supposed to
be involved in regulating the synthesis of very specialized mammalian
subcellular lysosome-related organelles such as platelet dense
granules, melanosomes, MHC II compartments, lytic granules, and
synaptic vesicles. Regarding the functional aspects of the novel HPS genes, several novel biogenesis of
lysosome-related organelle complexes (BLOC-1, BLOC-2, and BLOC-3) have been recently identified. That
is dysbindin, muted, pallidin, blos1, blos2, blos3, snapin, and cno in
BLOC-1 (Li W, et al. Nat Genet, 2003), coa/HPS3, ru2/HPS5, and ru/HPS6 in BLOC-2 (Zhang Q, et al. Nat Genet,2003; Gautam R, et al.J Biol Chem, 2004; Suzuki T, et al. Genomics, 2001), ep/HPS1 and le/HPS4
in BLOC-3 (Suzuki T, et al. Nat Genet, 2002). These complexes form a network in regulating endosomal to lysosomal transport (reviewed by Li W, et al. J Genet Genomics, 2007). The biochemical features and assembling machineries of these
complexes remain to be defined. In addition, two transporter encoding genes, Slc7a11 and Slc35d3, have been defined as genes involved in regulating trafficking and organelle development as their mutations mimic some phenotypes in HPS (Chintala S, et al. PNAS, 2005; Chintala S, et al. Blood, 2007).
The
short-term and long-term research goals are to:
(1) Define the unknown components or interactions
existing in the BLOCs.
(2) Dissect the cargo-specific endosomal transport mechanisms from the endosomes to the lysosomes mediated by these complexes, such as BLOCs, AP-3, HOPS, ESCRT.
(3) Define the biogenesis and the physiological roles of the specialized
Lysosome-Related Organelles (LRO), such as melanosomes, platelet dense granules, synaptic vesicles, Weibel-Palade bodies.
In the effort to reach these goals,
(1) We have further defined the role of dysbindin in the biogenesis and release of synaptic vesicles (Chen XW, et al. J Cell Biol, 2008), which may lead to the reduced transmission efficacy and therefore reproduce the schizophrenic symptoms in dysbindin-deficiency mice (Feng YQ, et al. Schizophr Res, 2008).
(2) We found JNK activation is involved in the process of cell death of Slc7a11/xCT-deficient cells (Qiao HX, et al. Biochem Biophys Res Comm, 2008). xCT is overexpressed in a variety of cancers. We found xCT is overexpressed in Kaposi's sarcoma and triggers the 14-3-3beta/ERK-mediated pathway in cell proliferation (Zeng Y, et al. Biol Rep, 2010). Furthermore, we first establish the role of xCT in tumor metastasis and implicate a potential target for cancer therapy (Chen RS, et al. Oncogene, 2009).
(3) We found that Pax3 transactivates the c-Kit promoter in controlling melanocyte development(Guo XL, et al. Pigment Cell Melanoma Res, 2010).
(4) We developed a novel text mining algorithm to predict the novel preotein-protein interactions (PPIs) (He M, et al. PLoS ONE, 2009).
2. Translational studies of HPS genes
As the mutations of the HPS genes lead to traffic jams causing albinism, neurodegeneration, schizophrenia and immunodeficiency, the translation of our research to clinical applications is to
(1) Study the genotype-phenotype relationship in albinism (Wang Y, et al. J Dermatol Sci, 2009; Wang Y, et al. Eur J Ophthalmol, 2009; Wei AH, et al. J Dermatol Sci, 2009; Wei AH, et al. J Invest Dermatol, 2010).
(2) Provide genetic counseling for these devastating diseases (He M and Li W. BMC Med Genet, 2007; He M and Li W. Yi Chuan, 2007).
(3) Search for new drug targets, such as xCT in tumor (Chen RS, et al. Oncogene, 2009), and dysbindin in schizophrenia (Feng YQ, et al. Schizophr Res, 2008).
(4) Identify novel disease-causative genes.