Upregulation of miR-23a∼27a∼24-2 Cluster Induces Caspase-Dependent and -Independent Apoptosis in Human Embryonic Kidney Cells

被引:128
作者
Chhabra, Ravindresh
Adlakha, Yogita K.
Hariharan, Manoj
Scaria, Vinod
Saini, Neeru
机构
[1] Institute of Genomics and Integrative Biology, Delhi
来源
PLOS ONE | 2009年 / 4卷 / 06期
关键词
D O I
10.1371/journal.pone.0005848
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
miRNAs have emerged as important players in the regulation of gene expression and their deregulation is a common feature in a variety of diseases, especially cancer. Currently, many efforts are focused on studying miRNA expression patterns, as well as miRNA target validation. Here, we show that the over expression of miR-23a similar to 27a similar to 24-2 cluster in HEK293T cells induces apoptosis by caspase-dependent as well as caspase-independent pathway as proved by the annexin assay, caspase activation, release of cytochrome-c and AIF (apoptosis inducing factor) from mitochondria. Furthermore, the over expressed cluster modulates the expression of a number of genes involved in apoptosis including FADD (Fas Associated protein with Death Domain). Bioinformatically, FADD is predicted to be the target of hsa-miR-27a and interestingly, FADD protein was found to be up regulated consistent with very less expression of hsa-miR-27a in HEK293T cells. This effect was direct, as hsa-miR-27a negatively regulated the expression of FADD 3'UTR based reporter construct. Moreover, we also showed that over expression of miR-23a similar to 27a similar to 24-2 sensitized HEK293T cells to TNF-alpha cytotoxicity. Taken together, our study demonstrates that enhanced TNF-alpha induced apoptosis in HEK293T cells by over expression of miR-23a similar to 27a similar to 24-2 cluster provides new insights in the development of novel therapeutics for cancer.
引用
收藏
页数:11
相关论文
共 53 条
[1]   Death receptors: Signaling and modulation [J].
Ashkenazi, A ;
Dixit, VM .
SCIENCE, 1998, 281 (5381) :1305-1308
[2]   MicroRNAs: Genomics, biogenesis, mechanism, and function (Reprinted from Cell, vol 116, pg 281-297, 2004) [J].
Bartel, David P. .
CELL, 2007, 131 (04) :11-29
[3]   Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death [J].
Boldin, MP ;
Goncharov, TM ;
Goltsev, YV ;
Wallach, D .
CELL, 1996, 85 (06) :803-815
[4]   Role of microRNAs in plant and animal development [J].
Carrington, JC ;
Ambros, V .
SCIENCE, 2003, 301 (5631) :336-338
[5]   MicroRNAs modulate hematopoietic lineage differentiation [J].
Chen, CZ ;
Li, L ;
Lodish, HF ;
Bartel, DP .
SCIENCE, 2004, 303 (5654) :83-86
[6]   TNF-R1 signaling: A beautiful pathway [J].
Chen, GQ ;
Goeddel, DV .
SCIENCE, 2002, 296 (5573) :1634-1635
[7]   Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis [J].
Cheng, AM ;
Byrom, MW ;
Shelton, J ;
Ford, LP .
NUCLEIC ACIDS RESEARCH, 2005, 33 (04) :1290-1297
[8]   OncomiRs: the discovery and progress of microRNAs in cancers [J].
Cho, William C. S. .
MOLECULAR CANCER, 2007, 6 (1)
[9]   Role of AIF in caspase-dependent and caspase-independent cell death [J].
Cregan, SP ;
Dawson, VL ;
Slack, RS .
ONCOGENE, 2004, 23 (16) :2785-2796
[10]   Mechanisms of translational control by the 3′ UTR in development and differentiation [J].
de Moor, CH ;
Meijer, H ;
Lissenden, S .
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2005, 16 (01) :49-58