miR-125b promotes cell death by targeting spindle assembly checkpoint gene MAD1 and modulating mitotic progression

• Published in: Cell death and differentiation Vol. 20; no. 3; pp. 430 - 442
• Main Authors: Bhattacharjya, S, Nath, S, Ghose, J, Maiti, G P, Biswas, N, Bandyopadhyay, S, Panda, C K, Bhattacharyya, N P, Roychoudhury, S
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.03.2013
• Subjects: 3' Untranslated Regions; adaptor proteins; Anaphase; Apoptosis; Base Sequence; Calcium-Binding Proteins - metabolism; Cancer; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell death; Cell Line, Tumor; Cell Proliferation; Chromosome Aberrations; Down-Regulation; HCT116 Cells; Hep G2 Cells; Humans; M Phase Cell Cycle Checkpoints; Mad2 Proteins; Metaphase; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Mitosis; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original Paper; Repressor Proteins - metabolism; Spindles; Stochasticity; Tumor cell lines
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2012.135

The spindle assembly checkpoint (SAC) is a 'wait-anaphase' mechanism that has evolved in eukaryotic cells in response to the stochastic nature of chromosome-spindle attachments. In the recent past, different aspects of the SAC regulation have been described. However, the role of microRNAs in the SAC is vaguely understood. We report here that Mad1, a core SAC protein, is repressed by human miR-125b. Mad1 serves as an adaptor protein for Mad2 - which functions to inhibit anaphase entry till the chromosomal defects in metaphase are corrected. We show that exogenous expression of miR-125b, through downregulation of Mad1, delays cells at metaphase. As a result of this delay, cells proceed towards apoptotic death, which follows from elevated chromosomal abnormalities upon ectopic expression of miR-125b. Moreover, expressions of Mad1 and miR-125b are inversely correlated in a variety of cancer cell lines, as well as in primary head and neck tumour tissues. We conclude that increased expression of miR-125b inhibits cell proliferation by suppressing Mad1 and activating the SAC transiently. We hypothesize an optimum Mad1 level and thus, a properly scheduled SAC is maintained partly by miR-125b.