RAF kinase inhibitory protein (RKIP) modulates cell cycle kinetics and motility

被引:42
作者
al-Mulla, Fahd [1 ]
Bitar, Milad S. [2 ]
Taqi, Zainab [1 ]
Rath, Oliver [3 ]
Kolch, Walter [3 ,4 ]
机构
[1] Kuwait Univ, Dept Pathol, Fac Med, Hlth Sci Ctr, Safat 13110, Kuwait
[2] Kuwait Univ, Dept Pharmacol, Fac Med, Hlth Sci Ctr, Safat 13110, Kuwait
[3] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland
[4] Univ Coll Dublin, Syst Biol Ireland & Conway Inst, Dublin, Ireland
基金
爱尔兰科学基金会;
关键词
ANAPHASE-PROMOTING COMPLEX/CYCLOSOME; PROSTATE-CANCER METASTASIS; COLORECTAL-CANCER; AURORA-B; HEPATOCELLULAR-CARCINOMA; TRANSCRIPTIONAL ACTIVITY; PROTEOMIC ANALYSIS; DEPENDENT KINASES; INDUCED APOPTOSIS; DNA-REPLICATION;
D O I
10.1039/c0mb00208a
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
RKIP-1 is a metastasis suppressor that is frequently downregulated in aggressive cancers. However, the consequences of RKIP loss in primary or immortalized cells have not yet been explored. Using HEK-293 RKIP depleted (termed HEK-499) and Flp-In T-Rex-293 RKIP inducible cell lines combined with whole transcriptome analysis, we show that RKIP-1 silencing accelerates DNA synthesis and G1/S transition entry by inducing the expression of cdc6, MCM 2, 4, 6, 7, cdc45L, cyclin D2, cyclin E2, cyclin D1, SKP2 and the downregulation of p21(cip1). Moreover, RKIP depletion accelerates the time from nuclear envelop breakdown (NEB) to anaphase markedly, while the upregulation of RKIP shortened the NEB to anaphase time. We show that RKIP depletion induces the expression of NEK6, a molecule known to enhance G2/M transition, and down-regulates G2/M checkpoint molecules like Aurora B, cyclin G1 and sertuin that slow the G2/M transition time. These subtle changes in the kinetics of the cell cycle culminate in a higher proliferation rate of HEK-499 compared to control cells. Finally, we show that RKIP depletion enhances cellular motility by inducing the expression/stabilization of beta-catenin, vimentin, MET and PAK1. Overall, our data suggest that modulation of the cell cycle checkpoints and motility by RKIP may be fundamental to its metastasis suppressive function in cancer and that RKIP role in a cell is more intricate and diverse than previously thought.
引用
收藏
页码:928 / 941
页数:14
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