Post-translational modification of HINT1 mediates activation of MITF transcriptional activity in human melanoma cells

A. Motzik, E. Amir, T. Erlich, J. Wang, B. G. Kim, Jung Min Han, J. H. Kim, H. Nechushtan, M. Guo, E. Razin, S. Tshori

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Abstract

Microphthalmia transcription factor (MITF) is a basic helix-loop-helix leucine zipper (bHLH-Zip) DNA-binding protein. This transcription factor plays a crucial role in the physiological and pathological functions of distinct cell types. MITF transcriptional activity is inhibited by the histidine triad nucleotide-binding protein 1 (HINT1) through direct binding. We previously reported that this association is disrupted by the binding of the second messenger Ap 4 A to HINT1. Ap 4 A is mainly produced in the mammalian cells by S207-phosphorylated Lysyl-tRNA synthetase. In this study, we found first that HINT1 was subjected to K21 acetylation and Y109 phosphorylation in activated mast cells, together with the Ap 4 A-triggered HINT1 dissociation from MITF. Mutational analysis confirmed that these modifications promote MITF transcriptional and oncogenic activity in melanoma cell lines, derived from human melanoma patients. Thus, we provided here an example that manipulation of the LysRS-Ap 4 A-HINT1-MITF signalling pathway in melanoma through post-translational modifications of HINT1 can affect the activity of the melanoma oncogene MITF.Oncogene advance online publication, 10 April 2017; doi:10.1038/onc.2017.81.

Original languageEnglish
JournalOncogene
DOIs
Publication statusAccepted/In press - 2017 Apr 10

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Motzik, A., Amir, E., Erlich, T., Wang, J., Kim, B. G., Han, J. M., Kim, J. H., Nechushtan, H., Guo, M., Razin, E., & Tshori, S. (Accepted/In press). Post-translational modification of HINT1 mediates activation of MITF transcriptional activity in human melanoma cells. Oncogene. https://doi.org/10.1038/onc.2017.81