title: A PREVIOUSLY UNKNOWN UNIQUE CHALLENGE FOR INHIBITORS OF SYK ATP-BINDING SITE: ROLE OF SYK AS A CELL CYCLE CHECKPOINT REGULATOR.
abstract: The identification of SYK as a molecular target in B-lineage leukemia/lymphoma cells prompted the development of SYK inhibitors as a new class of anti-cancer drug candidates. Here we report that induction of the SYK gene expression in human cells causes a significant down-regulation of evolutionarily conserved genes associated with mitosis and cell cycle progression providing unprecedented evidence that SYK is a master regulator of cell cycle regulatory checkpoint genes in human cells. We further show that SYK regulates the G2checkpoint by physically associating with and inhibiting the dual-specificity phosphatase CDC25C via phosporylation of its S216 residue. SYK depletion by RNA interference or treatment with the chemical SYK inhibitor prevented nocodazole-treated human cell lines from activating the G2checkpoint via CDC25C S216-phoshorylation and resulted in polyploidy. Our study provides genetic and biochemical evidence that spleen tyrosine kinase (SYK) has a unique role in the activation of the G2checkpoint in both nonlymphohematopoietic and B-lineage lymphoid cells. This previously unknown role of SYK as a cell cycle checkpoint regulator represents an unforeseen and significant challenge for inhibitors of SYK ATP binding site.
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027 ; Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA.
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027 ; Molecular Oncology Program, Parker Hughes Institute, St. Paul, MN 55113, USA; USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027 ; Molecular Oncology Program, Parker Hughes Institute, St. Paul, MN 55113, USA; USA.
authors.forename: Zahide
authors.initials: Z
authors.lastname: Ozer
authors.affiliation: Molecular Oncology Program, Parker Hughes Institute, St. Paul, MN 55113, USA; USA ; Department of Veterinary and Biomedical Science, University of Minnesota, St. Paul, MN 55108.
authors.forename: Patricia
authors.initials: P
authors.lastname: Goodman
authors.affiliation: Medicinal Bioinformatics Center, Shanghai Jiatong University.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027 ; Molecular Oncology Program, Parker Hughes Institute, St. Paul, MN 55113, USA; USA ; Department of Biology and Bioinformatics Program, Gustavus Adolphus College, 800 W College Avenue, St. Peter, MN 56082, USA.
authors.forename: Sanjive
authors.initials: S
authors.lastname: Qazi
keywords: Cell cycle; checkpoint control; genomnic instability; phosphatase; tyrosine kinase