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Interplay between Cdh1 and JNK activity during the cell cycle

Abstract

The ubiquitin ligase APC/CCdh1 coordinates degradation of key cell cycle regulators. We report here that a nuclear-localized portion of the stress-activated kinase JNK is degraded by the APC/CCdh1 during exit from mitosis and the G1 phase of the cell cycle. Expression of a non-degradable JNK induces prometaphase-like arrest and aberrant mitotic spindle dynamics. Moreover, JNK phosphorylates Cdh1 directly, during G2 and early mitosis, changing its subcellular localization and attenuating its ability to activate the APC/C during G2/M. This regulatory mechanism between JNK and Cdh1 reveals an important function for JNK during the cell cycle.

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Figure 1: JNK is degraded in vivo and in vitro in a cell cycle- and KEN box-dependent manner.
Figure 2: JNK levels are directly regulated by APC/CCdh1-mediated protein degradation during the cell cycle.
Figure 3: JNK activation during the cell cycle regulates its subcellular localization and degradation.
Figure 4: Unrestricted activation of JNK during cell cycle progression regulates Wee1's levels, Cdk1 activity, and entry into mitosis.
Figure 5: Hyperactivation of JNK during unperturbed cell cycle induces aberrant microtubular and chromosomal structures and a prometaphase-like arrest in cells.
Figure 6: JNK-mediated phosphorylation of Cdh1 regulates its function.
Figure 7: JNK phosphorylates Cdh1 in cells independently of CDKs activation.
Figure 8: JNK-mediated phosphorylation of Cdh1 affects cell cycle progression.

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Acknowledgements

We are indebted to R. Agami, M. Brandeis, J. Lukas, J. Bartek, J. Kyriakis, T. Hunter, H. Piwnica-Worms, S. Tsai, J. Hsieh, T. Lorca and O. Coux for essential reagents used in this work. Supports by NCI grant (CA78419) to Z.A.R. and the Sass foundation to G.J.G. are gratefully acknowledged.

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Z.A.R. and G.J.G. designed, and G.J.G. performed the experiments; T.T., W.J. and G.J.G. performed the microscopy; M.C. and G.J.G. conducted the FACS analyses; G.J.G. and Z.A.R. organized the study and wrote the paper.

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Correspondence to Ze'ev A. Ronai.

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Gutierrez, G., Tsuji, T., Chen, M. et al. Interplay between Cdh1 and JNK activity during the cell cycle. Nat Cell Biol 12, 686–695 (2010). https://doi.org/10.1038/ncb2071

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