Journal
EBIOMEDICINE
Volume 1, Issue 1, Pages 16-28Publisher
ELSEVIER
DOI: 10.1016/j.ebiom.2014.10.019
Keywords
Cell cycle; Tyrosine kinase; Phosphatase; Checkpoint control; Genomic instability
Funding
- DHHS grants from the National Cancer Institute [P30-CA-014089, U01-CA-151837, R01CA-154471]
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning
- DHHS [P30CA014089]
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The identification of SYK as a molecular target in B-lineage leukemia/lymphoma cells prompted the development of SYK inhibitors as a newclass 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 G(2) checkpoint by physically associating with and inhibiting the dual-specificity phosphatase CDC25C via phosphorylation 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 G2 checkpoint via CDC25C S216-phosphorylation 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 G2 checkpoint in both non-lymphohematopoietic 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. (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license
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