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Tethering by lamin A stabilizes and targets the ING1 tumour suppressor

Nature Cell Biology volume 10, pages 1333–1340 (2008)Cite this article

Abstract

ING proteins interact with core histones through their plant homeodomains (PHDs)1,2,3,4 and with histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes to alter chromatin structure5,6,7. Here we identify a lamin interaction domain (LID) found only in ING proteins, through which they bind to and colocalize with lamin A. Lamin knockout (LMNA−/−) cells show reduced levels of ING1 that mislocalize. Ectopic lamin A expression increases ING1 levels and re-targets it to the nucleus to act as an epigenetic regulator6,8. ING1 lacking the LID does not interact with lamin A or affect apoptosis. In LMNA−/− cells, apoptosis is not affected by ING1. Mutation of lamin A results in several laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS), a severe premature ageing disorder9. HGPS cells have reduced ING1 levels that mislocalize. Expression of LID peptides to block lamin A–ING1 interaction induces phenotypes reminiscent of laminopathies including HGPS9,10. These data show that targeting of ING1 to the nucleus by lamin A maintains ING1 levels and biological function. Known roles for ING proteins in regulating apoptosis and chromatin structure indicate that loss of lamin A–ING interaction may be an effector of lamin A loss, contributing to the HGPS phenotype.

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Figure 1: Structural features of ING1 and potential binding partners of the LID.
Figure 2: ING1 binds to lamin A through a LID.
Figure 3: ING1 localization in different model cell systems.
Figure 4: Lamin A affects ING1 levels and biological activity.
Figure 5: Overexpression of ING constructs affects nuclear morphology and induces senescence.

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Acknowledgements

We thank E. White for lamin constructs, J. Quarrie and D. Rancourt for ES cells, the SACRI Microscopy Facility for cell imaging, D. Boland and S. Law of the SAS for ING antibodies, D. Schreimer for LC/MS/MS advice and L. Robertson for help with flow cytometry. This study was supported by grants from the CIHR to K.R., from the NSERC to J.B.R. and to B.B. from the NIH. K.R. is a Scientist of the AHFMR, M.A.S. holds studentships from AHFMR and the Alberta Cancer Board (ACB) and H.S. and P.B. hold an ACB studentship.

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Author notes

  1. Brian E. Burke

    Present address: Department of Anatomy and Cell Biology, University of Florida College of Medicine, 1600 SW Archer Road, Gainesville, 32606, FL, USA

  2. Michelle S. Scott

    Present address: Current address: School of Life Sciences Research, College of Life Sciences, University of Dundee, Scotland.,

  3. Xijing Han and Xiaolan Feng: These authors contributed equally to the manuscript

Authors and Affiliations

  1. Departments of Biochemistry & Molecular Biology and Oncology, Faculty of Medicine, University of Calgary, 3330 Hospital Dr. NW, Calgary, T2N 4N1, Alberta, Canada

    Xijing Han, Xiaolan Feng, Heather Smith, Pinaki Bose, Keiko Suzuki, Mohamed A. Soliman & Karl Riabowol

  2. Departments of Cell Biology and Anatomy, Biochemistry & Molecular Biology and Oncology, Faculty of Medicine, University of Calgary, 3330 Hospital Dr. NW, Calgary, T2N 4N1, Alberta, Canada

    Jerome B. Rattner

  3. Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Mohamed A. Soliman

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Han, X., Feng, X., Rattner, J. et al. Tethering by lamin A stabilizes and targets the ING1 tumour suppressor. Nat Cell Biol 10, 1333–1340 (2008). https://doi.org/10.1038/ncb1792

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