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

Mukul Mathur1, Sharmistha Das, Herbert H Samuels

  • 1Departments of Pharmacology and Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. mukul.mathur@med.nyu.edu

Oncogene
|August 7, 2003
PubMed

Insights

The PSF-TFE3 fusion protein drives papillary renal cell carcinoma by trapping TFE3 and p53 outside the nucleus. Targeting this fusion protein offers a potential treatment strategy for this kidney cancer subset.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Papillary renal cell carcinomas (PRCC) are linked to chromosomal translocations involving the TFE3 gene.
  • These translocations result in chimeric proteins, including PSF-TFE3, which are implicated in cancer development.

Purpose of the Study:

  • To investigate the role of the PSF-TFE3 fusion protein in mediating cell transformation in PRCC.
  • To elucidate the subcellular localization and functional impact of PSF-TFE3.

Main Methods:

  • Utilized UOK-145 papillary renal carcinoma cells expressing endogenous PSF-TFE3.
  • Employed siRNA targeting the PSF-TFE3 fusion junction to assess its impact on protein localization and cellular function.
  • Compared the localization of wild-type TFE3, PSF, and the PSF-TFE3 chimera.

Main Results:

  • PSF-TFE3, unlike wild-type TFE3 and PSF, localizes to the endosomal compartment, not the nucleus.
  • PSF-TFE3 sequesters wild-type TFE3 and p53 in the cytoplasm, leading to functionally null extranuclear TFE3 and p53.
  • siRNA-mediated reduction of PSF-TFE3 restored nuclear localization of TFE3 and p53 in UOK-145 cells.

Conclusions:

  • PSF-TFE3 promotes cell transformation by exporting TFE3 and p53 from the nucleus to the cytoplasm for degradation.
  • This novel mechanism highlights PSF-TFE3 as a potential therapeutic target for a subset of renal cell carcinomas.

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