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The transcriptional coactivators megakaryoblastic leukemia 1/2 mediate the effects of loss of the tumor suppressor deleted in liver cancer 1

Oncogene volume 31, pages 3913–3923 (2012)Cite this article

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Abstract

Deleted in Liver Cancer 1 (DLC1) is a tumor suppressor whose allele is lost in 50% of liver, breast, lung and 70% of colon cancers. Here, we show that the transcriptional coactivators Megakaryoblastic Leukemia 1 and 2 (MKL1/2) are constitutively localized to the nucleus in hepatocellular and mammary carcinoma cells that lack DLC1. Moreover, DLC1 loss and MKL1 nuclear localization correlate in primary human hepatocellular carcinoma. Nuclear accumulation of MKL1 in DLC1-deficient cancer cells is accomplished by activation of the RhoA/actin signaling pathway and concomitant impairment of MKL1 phosphorylation, which results in constitutive activation of MKL1/2 target genes. We provide evidence that MKL1/2 mediates cancerous transformation in DLC1-deficient hepatocellular and mammary carcinoma cells. Depletion of MKL1/2 suppresses cell migration, cell proliferation and anchorage-independent cell growth induced by DLC1 loss.

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Acknowledgements

We thank Dr Scott Lowe for the DLC1 knockdown hepatocytes and Dr Monilola Olayioye for DLC1 vectors. Breast carcinoma cell lines were kindly provided by Dr Ramon Parsons. This work was funded by grant MU 2737/2-1 from the German Research Foundation (DFG) to SM and grant CA050329 from the National Cancer Institute to RP.

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Author notes

  1. T Gudermann and R Prywes: These authors contributed equally to this work.

Authors and Affiliations

  1. Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany

    S Muehlich, V Hampl, S Khalid, N Frank & T Gudermann

  2. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    S Singer & K Breuhahn

  3. Department of Biological Sciences, Columbia University, New York, NY, USA

    R Prywes

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  1. S Muehlich
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Correspondence to S Muehlich.

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Muehlich, S., Hampl, V., Khalid, S. et al. The transcriptional coactivators megakaryoblastic leukemia 1/2 mediate the effects of loss of the tumor suppressor deleted in liver cancer 1. Oncogene 31, 3913–3923 (2012). https://doi.org/10.1038/onc.2011.560

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