Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors

Bian, Yang; Kitagawa, Risa; Bansal, Parmil K.; Fujii, Yo; Stepanov, Alexander A.; Kitagawa, Katsumi

doi:10.1073/pnas.1315588111

Cited by 36 publications

(28 citation statements)

References 39 publications

(40 reference statements)

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“…Mad2 overexpression is a hallmark in many cancers, and PP2A inhibition has been suggested as a therapeutic means of targeting Mad2-overexpressing tumor cells. 16 Western blotting demonstrated that LB100 exhibited a concentration-dependent decrease in Mad2 expression in 143B cells (Fig. 2C).…”

Section: Lb100 Sensitizes Osteosarcoma Cells To the Cytotoxic Effectsmentioning

confidence: 93%

Inhibition of protein phosphatase 2A with the small molecule LB100 overcomes cell cycle arrest in osteosarcoma after cisplatin treatment

Zhang¹,

Hong

et al. 2015

Cell Cycle

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Section: Lb100 Sensitizes Osteosarcoma Cells To the Cytotoxic Effectsmentioning

confidence: 93%

Inhibition of protein phosphatase 2A with the small molecule LB100 overcomes cell cycle arrest in osteosarcoma after cisplatin treatment

Zhang¹,

Hong

et al. 2015

Cell Cycle

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“…Although SDL has been used to identify protein targets of enzymes (82,100,101) and to identify specific subsets of genes within chromosome segregation mutants (29), it is underused to uncover genetic contexts that could selectively target cancer cells with elevated levels of a specific gene (26,27,102). SDL screens therefore represent a powerful approach for fast and easy identification of candidate chemotherapeutic drug targets within the context of dCIN gene overexpression that could enable targeted elimination of these cells.…”

Section: Sdl Screens As a Platform To Identify Therapeutic Targets Inmentioning

confidence: 99%

“…Most SL approaches focus on exploiting specific somatic mutations or deletions in cancer driver genes; however, there are just as many amplified regions as deleted regions in cancer genomes (17). Thus, we propose using synthetic dosage lethality (SDL), which is SL with an amplified and/or overexpressed gene, as an approach to selectively target tumors that overexpress dCIN genes (26,27). SDL occurs when the overexpression of a gene is not lethal in a wild-type background but in conjunction with a second site nonlethal mutation causes lethality (28)(29)(30).…”

mentioning

confidence: 99%

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

Duffy

Fam

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors.dosage chromosome instability | overexpression | synthetic dosage lethality | TDP1 | rhabdomyosarcoma

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“…Our results showed that co-transfection of a MAD2 expression plasmid 10 (that is RNAi-resistant in our system) can rescue the phosphorylation of histone H3S28 in MAD2-silenced HeLa cells. The recovery in the level of histone H3 phosphorylation was comparable to the control cells (Fig.…”

Section: Mad2 Regulates Aurora B-mediated Mitotic Phosphorylation Of mentioning

confidence: 64%

Regulation of AURORA B function by mitotic checkpoint protein MAD2

2016

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Cell cycle checkpoint signaling stringently regulates chromosome segregation during cell division. MAD2 is one of the key components of the spindle and mitotic checkpoint complex that regulates the fidelity of cell division along with MAD1, CDC20, BUBR1, BUB3 and MAD3. MAD2 ablation leads to erroneous attachment of kinetochore-spindle fibers and defective chromosome separation. A potential role for MAD2 in the regulation of events beyond the spindle and mitotic checkpoints is not clear. Together with active spindle assembly checkpoint signaling, AURORA B kinase activity is essential for chromosome condensation as cells enter mitosis. AURORA B phosphorylates histone H3 at serine 10 and serine 28 to facilitate the formation of condensed metaphase chromosomes. In the absence of functional AURORA B cells escape mitosis despite the presence of misaligned chromosomes. In this study we report that silencing of MAD2 results in a drastic reduction of metaphase-specific histone H3 phosphorylation at serine 10 and serine 28. We demonstrate that this is due to mislocalization of AURORA B in the absence of MAD2. Conversely, overexpression of MAD2 concentrated the localization of AURORA B at the metaphase plate and caused hyper-phosphorylation of histone H3. We find that MAD1 plays a minor role in influencing the MAD2-dependent regulation of AURORA B suggesting that the effects of MAD2 on AURORA B are independent of the spindle checkpoint complex. Our findings reveal that, in addition to its role in checkpoint signaling, MAD2 ensures chromosome stability through the regulation of AURORA B.

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Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors

Cited by 36 publications

References 39 publications

Inhibition of protein phosphatase 2A with the small molecule LB100 overcomes cell cycle arrest in osteosarcoma after cisplatin treatment

Inhibition of protein phosphatase 2A with the small molecule LB100 overcomes cell cycle arrest in osteosarcoma after cisplatin treatment

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

Regulation of AURORA B function by mitotic checkpoint protein MAD2

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