Human Sgo1 downregulation leads to chromosomal instability in colorectal cancer

Iwaizumi, Moriya; Shinmura, Kazuya; Mori, Hiroki; Yamada, Hidetaka; Suzuki, Mitsuaki; Kitayama, Yasuhiko; Igarashi, Hisaki; Nakamura, Takamitsu; Suzuki, Hideaki; Watanabe, Yoshinori; Hishida, Akira; Ikuma, Mutsuhiro; Sugimura, Haruhiko

doi:10.1136/gut.2008.149468

Cited by 80 publications

(87 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Depletion of shugoshin results in premature separation of sister chromatids and aneuploidy in human colon cancer cells (Iwaizumi et al, 2009). It could be conjectured that removal or lack of centromere cohesin causes aneuploidy.…”

Section: Discussionmentioning

confidence: 99%

Loss of STAG2 causes aneuploidy in normal human bladder cells

Li¹,

Zhang²,

Tang³

et al. 2015

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. The aim of this study was to determine how the function of human stromal antigen 2 (STAG2) plays an important role in proper chromosome separation. STAG2 mRNA in normal bladder cells and bladder tumor cells was evaluated by RT-PCR. The protein levels of STAG2 in normal bladder cells and bladder tumor cells were determined Loss of STAG2 function in cells by western blot. A cell proliferation assay was used to measure the growth of tumor cells and STAG2-inhibited normal cells, and STAG2-inhibited normal cells were subjected to karyotype analysis. Both STAG-2 mRNA and protein expression levels were lower in bladder cancer cells compared to the controls. Knockdown of STAG2 caused aneuploidy in normal bladder cells, leading to a decreased expression of the cohesin complex components SMC1, SMC3 and RAD21, but there was no obvious effect of STAG2 knockdown on cell proliferation. Our study indicated that abnormal expression of STAG2 could cause aneuploidy in normal bladder cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Loss of STAG2 causes aneuploidy in normal human bladder cells

Li¹,

Zhang²,

Tang³

et al. 2015

Genet. Mol. Res.

View full text Add to dashboard Cite

show abstract

“…Sgo1 −/+ model has shown unique transcriptomic signatures at the tissue/organ level and cancer proneness in certain organs including colon, lung, and liver (Rao et al., 2016; Yamada et al., 2012, 2015, 2016). In humans, the homolog SgoL1 is frequently mutated or abnormally expressed in cancers, affecting the mitotic process (Iwaizumi et al., 2009; Kahyo et al., 2011; Matsuura et al., 2013; Wang et al., 2015). Congenital mutations in human SgoL1 lead to chronic atrial and intestinal dysrhythmia syndrome, affecting the heart and gut rhythm (Chetaille et al., 2014).…”

Section: Introductionmentioning

confidence: 99%

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

et al. 2018

View full text Add to dashboard Cite

SummarySpontaneous late‐onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early‐onset AD (EOAD) models that rely on forcible expression of AD‐associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limitation in AD modeling may contribute to the high failure rate of AD drugs in clinical trials. In this study, we hypothesized that genomic instability facilitates development of LOAD and tested two genomic instability mice models in the brain pathology at the old age. Shugoshin‐1 (Sgo1) haploinsufficient (∓) mice, a model of chromosome instability (CIN) with chromosomal and centrosomal cohesinopathy, spontaneously exhibited a major feature of AD pathology; amyloid beta accumulation that colocalized with phosphorylated Tau, beta‐secretase 1 (BACE), and mitotic marker phospho‐Histone H3 (p‐H3) in the brain. Another CIN model, spindle checkpoint‐defective BubR1−/+ haploinsufficient mice, did not exhibit the pathology at the same age, suggesting the prolonged mitosis‐origin of the AD pathology. RNA‐seq identified ten differentially expressed genes, among which seven genes have indicated association with AD pathology or neuronal functions (e.g., ARC, EBF3). Thus, the model represents a novel model that recapitulates spontaneous LOAD pathology in mouse. The Sgo1−/+ mouse may serve as a novel tool for investigating mechanisms of spontaneous progression of LOAD pathology, for early diagnosis markers, and for drug development.

show abstract

“…Shugoshin-like (SGOL1) protein, the mammalian homolog of shugoshin, interacts with protein phosphatase 2A (PP2A), localizes in the centromeric region and prevents cohesin complex from precocious cleavage at the centromere through dephosphorylation of SA2, one of the cohesin subunits (Kitajima et al, 2006;Riedel et al, 2006). In a study on human cancer, we found that SGOL1 expression was decreased in colorectal cancer and that SGOL1-knockdown led to CIN in a colon cancer cell line (Iwaizumi et al, 2009). Furthermore, a crucial link between histone H2A phosphorylation and CIN through shugoshin has recently been discovered (Kawashima et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…RT-PCR was carried out as described in our previous report (Iwaizumi et al, 2009). The primer sequences used for the first RT-PCR ( Figure 1b) were 5 0 -GGAGGAGGAAGATAG CTGTTGC-3 0 (sense) and 5 0 -TATGGCAATGGCTCACTC TG-3 0 (antisense).…”

Section: Rt-pcr and Plasmid Constructionmentioning

confidence: 99%

“…A primer targeting the junction between exon 2 and exon 4 was constructed for routine detection of SGOL1-P1 transcripts in specimens (Supplementary Figure S1). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was amplified as an internal control, and the quantitative real-time RT-PCR was carried out as described previously (Iwaizumi et al, 2009). To express SGOL1-P1 in mammalian cells, six myc tags were fused to the N-terminus of SGOL1-P1 and the product was inserted into pcDNA3.1.…”

Section: Rt-pcr and Plasmid Constructionmentioning

confidence: 99%

See 1 more Smart Citation

A novel tumor-derived SGOL1 variant causes abnormal mitosis and unstable chromatid cohesion

et al. 2011

Self Cite

View full text Add to dashboard Cite

Mitosis is the most conspicuous cell cycle phase, because it is the phase in which the dynamic physical distributions of cellular components into the two daughter cells occur. The separation of sister chromatids is especially important during mitosis, because of the extreme accuracy required for distribution to the next generation of cells. Shugoshinlike 1 (SGOL1) is a key protein in protecting sister chromatids from precocious separation. We have reported finding that chromosome instability is more likely in SGOL1-downregulated colorectal cancers, but it is still unknown whether there is an association between cancer and SGOL1 transcript variation. Here, we identified a novel SGOL1 variant, SGOL1-P1, in human colon cancer. The SGOL1-P1 transcript contains an exon-skip of exon 3 that results in a stop codon occurring within exon 4. Overexpression of SGOL1-P1 in HCT116 cells resulted in an increased number of cells with aberrant chromosome alignment, precociously separated chromatids and delayed mitotic progression, occasionally followed by inaccurate distribution of the chromosomes. These phenotypes, observed when SGOL1-P1 was present, were also observed very frequently in SGOL1-knockdown cells. Furthermore, the overexpression of SGOL1-P1 inhibited the localization of endogenous SGOL1 and cohesin subunit RAD21/SCC1 to the centromere. These results suggest that SGOL1-P1 may function as a negative factor to native SGOL1, and that abundant expression of SGOL1-P1 may be responsible for chromosomal instability.

show abstract

Human Sgo1 downregulation leads to chromosomal instability in colorectal cancer

Abstract: These findings suggest that hSgo1-downregulated colorectal cancers have a clinicopathological character of CIN, and hSgo1 downregulation leads to CIN in colorectal cancer cells.

Cited by 80 publications

References 35 publications

Loss of STAG2 causes aneuploidy in normal human bladder cells

Loss of STAG2 causes aneuploidy in normal human bladder cells

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

A novel tumor-derived SGOL1 variant causes abnormal mitosis and unstable chromatid cohesion

Contact Info

Product

Resources

About