当前位置： SCI文献检索 > EBioMedicine期刊下所有文献 > A PREVIOUSLY UNKNOWN UNIQUE CHALLENGE FOR INHIBITORS OF SYK ATP-BINDING SITE: ROLE OF SYK AS A CELL CYCLE CHECKPOINT REGULATOR.

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 G2 checkpoint 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 G2 checkpoint 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 G2 checkpoint 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.

journal_name

EBioMedicine

journal_title

EBioMedicine

authors

Uckun FM,Ma H,Ozer Z,Goodman P,Zhang J,Qazi S

doi

10.1016/j.ebiom.2014.10.019

subject

Has Abstract

pub_date

2014-11-01 00:00:00

pages

16-28

issue

1

issn

2352-3964

journal_volume

1

pub_type

杂志文章

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