title: WSB1: from homeostasis to hypoxia.
abstract: The wsb1 gene has been identified to be important in developmental biology and cancer. A complex transcriptional regulation of wsb1 yields at least three functional transcripts. The major expressed isoform, WSB1 protein, is a substrate recognition protein within an E3 ubiquitin ligase, with the capability to bind diverse targets and mediate ubiquitinylation and proteolytic degradation. Recent data suggests a new role for WSB1 as a component of a neuroprotective pathway which results in modification and aggregation of neurotoxic proteins such as LRRK2 in Parkinson's Disease, via an unusual mode of protein ubiquitinylation.WSB1 is also involved in thyroid hormone homeostasis, immune regulation and cellular metabolism, particularly glucose metabolism and hypoxia. In hypoxia, wsb1 is a HIF-1 target, and is a regulator of the degradation of diverse proteins associated with the cellular response to hypoxia, including HIPK2, RhoGDI2 and VHL. Major roles are to both protect HIF-1 function through degradation of VHL, and decrease apoptosis through degradation of HIPK2. These activities suggest a role for wsb1 in cancer cell proliferation and metastasis. As well, recent work has identified a role for WSB1 in glucose metabolism, and perhaps in mediating the Warburg effect in cancer cells by maintaining the function of HIF1. Furthermore, studies of cancer specimens have identified dysregulation of wsb1 associated with several types of cancer, suggesting a biologically relevant role in cancer development and/or progression.Recent development of an inducible expression system for wsb1 could aid in the further understanding of the varied functions of this protein in the cell, and roles as a potential oncogene and neuroprotective protein.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.|Department of Oncology, University of Calgary, Calgary, AB, T2N 4N1, Canada.|Department of Medical Biochemistry, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors.forename: Moinul
authors.initials: M
authors.lastname: Haque
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.|Department of Oncology, University of Calgary, Calgary, AB, T2N 4N1, Canada.|Department of Medical Biochemistry, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors.forename: Joseph Keith
authors.initials: JK
authors.lastname: Kendal
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.|Department of Oncology, University of Calgary, Calgary, AB, T2N 4N1, Canada.|Department of Medical Biochemistry, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors.forename: Ryan Matthew
authors.initials: RM
authors.lastname: MacIsaac
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada. demetric@ucalgary.ca.|Department of Oncology, University of Calgary, Calgary, AB, T2N 4N1, Canada. demetric@ucalgary.ca.|Department of Medical Biochemistry, University of Calgary, Calgary, AB, T2N 4N1, Canada. demetric@ucalgary.ca.|Calgary Laboratory Services, Room 302, HMRB, 3330 Hospital Dr. N.W., Calgary, AB, T2N 4N1, Canada. demetric@ucalgary.ca.
authors.forename: Douglas James
authors.initials: DJ
authors.lastname: Demetrick
mesh_terms: D000818:Animals; D006706:Homeostasis; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D011506:Proteins; C120287:WSB1 protein, human; D044767:Ubiquitin-Protein Ligases; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
keywords: Cancer; E3 ubiquitin ligase; HIPK2; Hypoxia; VHL; WSB1