SUMMARY Autophagy is an important intracellular catabolic mechanism that mediates the degradation of cytoplasmic proteins and organelles. We report a potent small molecule inhibitor of autophagy named “spautin-1” for specific and potent autophagy inhibitor-1. Spautin-1 promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two ubiquitin-specific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes. Beclin1 is a tumor suppressor and frequently monoallelically lost in human cancers. Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. Since USP10 mediates the deubiquitination of p53, regulating deubiquitination activity of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. Our study provides a molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1, and a potent small molecule inhibitor of autophagy as a possible lead compound for developing anticancer drugs.

) relating to the article 'Chromosomal breaks during mitotic catastrophe trigger γH2AX-ATM-p53-mediated apoptosis' by Gabriela Imreh, Helin Vakifahmetoglu Norberg, Stefan Imreh and Boris Zhivotovsky. J. Cell Sci. 2011Sci. 124, 2951Sci. -2963Sci. (doi: 10.1242).Concerns were raised regarding some of the data in Fig. 1A of the above-named paper. An investigation carried out by Karolinska Institutet concluded that no wrongdoing had occurred, and that no further action was required. An in-house review of the original data by Journal of Cell Science reached a similar conclusion.Journal of Cell Science is publishing this Note to alert readers that the concerns raised about this paper have been resolved. This course of action follows the advice set out by COPE (Committee on Publication Ethics), of which Journal of Cell Science is a member. Concerns have been raised regarding some of the data in Fig. 1A of the above-named paper. Journal of Cell Science is publishing this note to make readers aware of this issue, and we will provide further information once the issue has been resolved. 3419This course of action follows the advice set out by COPE (Committee on Publication Ethics), of which Journal of Cell Science is a member. There was an error published in J. Cell Sci. 124, 2951-2963. 1979In Fig. 4C, the blot representing pATM was inadvertently duplicated as representing G3PDH. The G3PDH western blot has been replaced with the correct image in the figure shown below. There are no changes to the figure legend, which is accurate. This error does not affect the conclusions of the study.The authors apologise to the readers for any confusion that this error might have caused. Fig. 4. Increased γH2AX level during MC leads to cell death. Untreated or doxorubicin (600 nM)-treated 14-3-3σ-knockout HCT116 cells were cultured and harvested at indicated time points and analysed by western blot (50 μg), comet assay and immunostaining using antibodies directed against γH2AX (green). Blots were reprobed for G3PDH to confirm an equal loading of the samples. The co-staining of nuclei was performed using Hoechst 33342 (white). (A,B) Representative confocal images showing nuclear morphology and γH2AX staining in 14-3-3σ-knockout HCT116 (A) or wild-type HCT116 (B) cells after treatment for indicated time. (C) 14-3-3σ-knockout HCT116 cells were treated for 9 hours with doxorubicin after which the culture medium was replaced and cells were grown for an additional 24, 48 and 72 hours. Immunoblots of p53, phosphorylated ATM and γH2AX are shown. (D) Doxorubicin-induced DNA damage measured by alkaline comet assay. Cells were analysed by fluorescence microscopy and scored according to tail moment. Error bars represent the mean of three independent experiments±s.e.m. Scale bar: 20 μm. Science (2016Science ( ) 129, 1950Science ( doi:10.1242 © 2016. Published by The Company of Biologists Ltd | Journal of Cell Journal of Cell ScienceChromosomal breaks during mitotic catastrophe trigger cH2AX-ATM-p53-mediated apoptosis Summary Although the cause...

There was an error published in J. Cell Sci. 124, 2951-2963.In Fig. 4C, the blot representing pATM was inadvertently duplicated as representing G3PDH. The G3PDH western blot has been replaced with the correct image in the figure shown below. There are no changes to the figure legend, which is accurate. This error does not affect the conclusions of the study.The authors apologise to the readers for any confusion that this error might have caused. Fig. 4. Increased γH2AX level during MC leads to cell death. Untreated or doxorubicin (600 nM)-treated 14-3-3σ-knockout HCT116 cells were cultured and harvested at indicated time points and analysed by western blot (50 μg), comet assay and immunostaining using antibodies directed against γH2AX (green). Blots were reprobed for G3PDH to confirm an equal loading of the samples. The co-staining of nuclei was performed using Hoechst 33342 (white). (A,B) Representative confocal images showing nuclear morphology and γH2AX staining in 14-3-3σ-knockout HCT116 (A) or wild-type HCT116 (B) cells after treatment for indicated time. (C) 14-3-3σ-knockout HCT116 cells were treated for 9 hours with doxorubicin after which the culture medium was replaced and cells were grown for an additional 24, 48 and 72 hours. Immunoblots of p53, phosphorylated ATM and γH2AX are shown. (D) Doxorubicin-induced DNA damage measured by alkaline comet assay. Cells were analysed by fluorescence microscopy and scored according to tail moment. Error bars represent the mean of three independent experiments±s.e.m. Scale bar: 20 μm. 1950

No abstract