Abstract
The mitotic spindle assembly checkpoint (SAC) is an essential control system of the cell cycle that contributes to mantain the genomic stability of eukaryotic cells. SAC genes expression is often deregulated in cancer cells, leading to checkpoint impairment and chromosome instability. The mechanisms responsible for the transcriptional regulation and deregulation of these genes are still largely unknown. Herein we identify the nonhistone architectural nuclear proteins High Mobility Group A1 (HMGA1), whose overexpression is a feature of several human malignancies and has a key role in cancer progression, as transcriptional regulators of SAC genes expression. In particular, we show that HMGA1 proteins are able to increase the expression of the SAC genes Ttk, Mad2l1, Bub1 and Bub1b, binding to their promoter regions. Consistently, HMGA1-depletion induces SAC genes downregulation associated to several mitotic defects. In particular, we observed a high number of unaligned chromosomes in metaphase, a reduction of prometaphase time, a delay of anaphase, a higher cytokinesis time and a higher percentage of cytokinesis failure by using live-cell microscopy. Finally, a significant direct correlation between HMGA1 and SAC genes expression was detected in human colon carcinomas indicating a novel mechanism by which HMGA1 contributes to cancer progression.
Highlights
The High Mobility Group A (HMGA) protein family is comprised of three proteins: HMGA1a and HMGA1b, which are encoded by the High Mobility Group A1 (HMGA1) gene through alternative splicing [1], and the related HMGA2 protein, encoded by a distinct gene [2]
We report that HMGA1 increases the transcription of budding uninhibited by benzimidazoles 1 (Bub1), Bub1b, mitotic arrest deficient-like 1 (Mad2l1) and Mps1/Ttk genes involved in the spindle assembly checkpoint (SAC)
HMGA1 increases the transcription of Bub1, Bub1b, Mad2l1 and Ttk genes involved in the SAC
Summary
The High Mobility Group A (HMGA) protein family is comprised of three proteins: HMGA1a and HMGA1b, which are encoded by the HMGA1 gene through alternative splicing [1], and the related HMGA2 protein, encoded by a distinct gene [2]. The involvement of HMGA proteins in embryogenesis, cell proliferation, differentiation, apoptosis and, above all, cancer development has been extensively demonstrated [3]. It has been previously demonstrated that HMGA proteins have oncogenic activity since their overexpression leads to the transformation of rat fibroblasts [7] and human epithelial breast cells [8], and transgenic mice overexpressing the HMGA proteins develop multiple neoplasias [9,10,11,12,13]
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