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Aberrant cytoplasmic localization of ARID1B activates ERK signaling and promotes oncogenesis
- Source :
- Journal of Cell Science.
- Publication Year :
- 2020
- Publisher :
- The Company of Biologists, 2020.
-
Abstract
- The ARID1B/BAF250b subunit of the human SWI/SNF chromatin remodeling complex is a canonical nuclear tumor suppressor. We employed in silico prediction, intracellular fluorescence and cellular fractionation based subcellular localization analyses to identify the ARID1B nuclear localization signal. A cytoplasm-restricted ARID1B-NLS mutant was significantly compromised in its canonical transcription activation and tumor suppressive functions, as expected. Surprisingly however, cytoplasmic localization appeared to induce a gain of oncogenic function in ARID1B as evidenced from several cell line and mouse xenograft based assays. Mechanistically, cytoplasm-localized ARID1B could bind c-RAF and PPP1CA causing stimulation of RAF-ERK signaling and β-catenin transcription activity. ARID1B harboring NLS mutations derived from tumor samples also exhibited aberrant cytoplasmic localization and acquired a neo-morphic oncogenic function via activation of RAF-ERK signaling. Further, immunohistochemistry on a tissue microarray revealed significant correlation of ARID1B cytoplasmic localization with increased levels of active forms of ERK1/2 and β-catenin as well as with advanced tumor stage and lymph node positivity in human primary pancreatic tumor tissues. ARID1B therefore promotes oncogenesis through cytoplasm-based gain of function mechanisms in addition to dysregulation in the nucleus.
- Subjects :
- Cytoplasm
Carcinogenesis
MAP Kinase Signaling System
Biology
medicine.disease_cause
Chromatin remodeling
03 medical and health sciences
0302 clinical medicine
Transcription (biology)
Protein Phosphatase 1
medicine
Humans
NLS
c-Raf
beta Catenin
030304 developmental biology
Cell Nucleus
0303 health sciences
Cell Biology
Subcellular localization
Cell biology
DNA-Binding Proteins
030220 oncology & carcinogenesis
Nuclear localization sequence
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 14779137 and 00219533
- Database :
- OpenAIRE
- Journal :
- Journal of Cell Science
- Accession number :
- edsair.doi.dedup.....6f4a2367e1988eb3b408d65f27ac9f60