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Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

Abstract

Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.

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Acknowledgements

We are grateful to S Chokshi, R Williams and J Dyson for critical comments on the manuscript. We also thank D Trono (Ecole Polytechnique Fédérale de Lausanne, Switzerland) for the pWPI lentiviral vector and M Johns (Imperial College) for the human PARP14 cDNA; H Cooksley, A Riva (Institute of Hepatology), and PM Choy, MH Lam and V Patel (MSc students) for technical support. GF receives funding from NIH grants R01 CA084040 and R01 CA098583 and Cancer Research UK grant C26587/A8839. DOH receives professorial support from the British Heart Foundation. This study was primarily supported by a research grant from Kay Kendall Leukemia Fund (KKL443) to CB, and in part by grants from Italian Association for Cancer Research (Start-up 8557) and the Foundation for Liver Research to S.P.

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Correspondence to S Papa or C Bubici.

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Barbarulo, A., Iansante, V., Chaidos, A. et al. Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma. Oncogene 32, 4231–4242 (2013). https://doi.org/10.1038/onc.2012.448

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Keywords

  • PARP14
  • c-Jun N-terminal kinase
  • survival
  • multiple myeloma
  • apoptosis

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