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TMF/ARA160 is a BC-box-containing protein that mediates the degradation of Stat3

Oncogene volume 23, pages 8908–8919 (2004)Cite this article

Abstract

TMF/ARA160 is a Golgi resident protein whose cellular functions have not been conclusively revealed. Herein we show that TMF/ARA160 can direct the proteasomal degradation of the key cell growth regulator – Stat3. TMF/ARA160 was dispersed in the cytoplasm of myogenic C2C12 cells that were grown under low-serum conditions. The cytoplasmic distribution of TMF/ARA160 was accompanied by its transient association with the tyrosine kinase Fer and with Stat3, which underwent proteasomal degradation under those conditions. Moreover, serum deprivation induced the association of ubiquitinated proteins, with the TMF/ARA160 complex. However, TMF/ARA160 did not bind Stat1, whose cellular levels were increased in serum-starved C2C12 cells. Amino-acid sequence analysis identified a BC-box element in TMF/ARA160 that mediated the binding of this protein to elongin C. Ectopic expression of TMF/ARA160 in serum-starved C2C12 cells drove the ubiquitination and proteasomal degradation of Stat3, an effect that was not caused by TMF/ARA160 devoid of the BC-box motif. Thus, the Golgi apparatus harbors a novel BC-box-containing protein that can direct Stat3 to proteasomal degradation. Interestingly, the level of TMF/ARA160 was significantly decreased in malignant brain tumors, implying a suppressive role of that protein in tumor progression.

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Abbreviations

Stat3:

signal transducer and activator of transcription 3

HIV1:

human immunodeficiency 1

LTR:

long-terminal repeat

AR:

androgen receptor

DMEM:

Dulbecco's modified Eagle's medium

FCS:

fetal calf serum

PBS:

phosphate-buffered saline

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Acknowledgements

We thank Professor Chaya Brodie for making the Meningioma tumors available to us and Ms A Goldreich for typing this manuscript. This work was supported by grants from the Israel Cancer Research Fund; the Melul Foundation; the Israel Cancer Association in memory of the late Professor N Trainin, from the Weinkselbaum Family Research Fund, a grant from CaPCURE Israel, and a grant from the Horowitz Foundation.

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Authors and Affiliations

  1. Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 52900, Israel

    Erez Perry, Rachel Tsruya, Oz Pomp, Michal Taller, Shira Weisberg, Hana Malovani, Sally Shpungin & Uri Nir

  2. Department of Oncology, Rabin Medical Center, Belinson Campus, Petach-Tikva, Israel

    Pavel Levitsky

  3. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Wendy Parris, Sarang Kulkarni & Tony Pawson

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Correspondence to Uri Nir.

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Perry, E., Tsruya, R., Levitsky, P. et al. TMF/ARA160 is a BC-box-containing protein that mediates the degradation of Stat3. Oncogene 23, 8908–8919 (2004). https://doi.org/10.1038/sj.onc.1208149

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