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PSF-TFE3 oncoprotein in papillary renal cell carcinoma inactivates TFE3 and p53 through cytoplasmic sequestration

Oncogene volume 22, pages 5031–5044 (2003)Cite this article

Abstract

Papillary renal cell carcinomas are associated with chromosomal translocations involving the helix–loop–helix leucine-zipper region of the TFE3 gene on the X chromosome. These translocations lead to the expression of TFE3 chimeras of PRCC, RCC17, NonO and PSF (PTB-associated splicing factor). In this study, we explored the role of PSF-TFE3 fusion protein in mediating cell transformation. Unlike wild-type TFE3 or PSF, which are nuclear proteins, PSF-TFE3 is not a nuclear protein and is targeted to the endosomal compartment. Although PSF-TFE3 has no effect on the nuclear localization of wild-type PSF, it sequesters wild-type TFE3 as well as p53 in the extranuclear compartment leading to functionally null p53 and TFE3 cells. In UOK-145 papillary renal carcinoma cells, which endogenously express PSF-TFE3, siRNA complementary to the PSF-TFE3 fusion junction leads to a reduction in PSF-TFE3 and redistribution of endogenous TFE3 and p53 from the cytoplasmic compartment to the nucleus. Our results indicate that PSF-TFE3 acts through a novel mechanism, and exports TFE3, p53 and possibly other factors from the nucleus to the cytoplasm for degradation leading to the transformed phenotype. Thus, PSF-TFE3 is a promising target for the treatment for a subset of renal cell carcinomas.

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Acknowledgements

Plasmid expressing GFP-TFE3 was kindly provided by Graham Goodwin. We thank Tom Kadesch for TFE3 expression vectors and TFE3-specific reporter constructs, Kathryn Calame for TFE3 antibody and Philip Tucker for PSF antibody. We also thank Colin S Cooper for the UOK-145 cell line and WM Linehan for UOK-109 cells. At NYU, we are grateful to David Sabatini and Milton Adesnik for helpful discussions, to Mel Rosenfeld for helping us with the endosome preparations, and to Mark Philips and David Michaelson for their help with confocal microscopy. This research was supported by NIH Grants DK16636 (HHS) and AR02083 (MM). HHS is a member of the NYUMC Cancer Center (CA16087).

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  1. Departments of Pharmacology and Medicine, New York University School of Medicine, 550 First Avenue, New York, 10016, NY, USA

    Mukul Mathur, Sharmistha Das & Herbert H Samuels

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  1. Mukul Mathur
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Correspondence to Mukul Mathur or Herbert H Samuels.

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Mathur, M., Das, S. & Samuels, H. PSF-TFE3 oncoprotein in papillary renal cell carcinoma inactivates TFE3 and p53 through cytoplasmic sequestration. Oncogene 22, 5031–5044 (2003). https://doi.org/10.1038/sj.onc.1206643

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