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PCGF2 negatively regulates arsenic trioxide-induced PML-RARA protein degradation via UBE2I inhibition in NB4 cells
- Source :
- Biochimica et biophysica acta. 1863(7 Pt)
- Publication Year :
- 2015
-
Abstract
- Arsenic trioxide (ATO) is a therapeutic agent for acute promyelocytic leukemia (APL) which induces PML-RARA protein degradation via enhanced UBE2I-mediated sumoylation. PCGF2, a Polycomb group protein, has been suggested as an anti-SUMO E3 protein by inhibiting the sumoylation of UBE2I substrates, HSF2 and RANGAP1, via direct interaction. Thus, we hypothesized that PCGF2 might play a role in ATO-induced PML-RARA degradation by interacting with UBE2I. PCGF2 protein was down-regulated upon ATO treatment in human APL cell line, NB4. Knockdown of PCGF2 in NB4 cells, in the absence of ATO treatment, was sufficient to induce sumoylation-, ubiquitylation- and PML nuclear body-mediated degradation of PML-RARA protein. Moreover, overexpression of PCGF2 protected ATO-mediated degradation of ectopic and endogenous PML-RARA in 293T and NB4 cells, respectively. In 293T cells, UBE2I-mediated PML-RARA degradation was reduced upon PCGF2 co-expression. In addition, UBE2I-mediated sumoylation of PML-RARA was reduced upon PCGF2 co-expression and PCGF2-UBE2I interaction was confirmed by co-immunoprecipitation. Likewise, endogenous PCGF2-UBE2I interaction was detected by co-immunoprecipitation and immunofluorescence assays in NB4 cells. Intriguingly, upon ATO-treatment, such interaction was disrupted and UBE2I was co-immunoprecipitated or co-localized with its SUMO substrate, PML-RARA. Taken together, our results suggested a novel role of PCGF2 in ATO-mediated degradation of PML-RARA that PCGF2 might act as a negative regulator of UBE2I via direct interaction.
- Subjects :
- 0301 basic medicine
Acute promyelocytic leukemia
Time Factors
Oncogene Proteins, Fusion
SUMO protein
Fluorescent Antibody Technique
Antineoplastic Agents
Protein degradation
Transfection
Arsenicals
Gene Expression Regulation, Enzymologic
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Ubiquitin
Arsenic Trioxide
Leukemia, Promyelocytic, Acute
Cell Line, Tumor
medicine
Humans
Immunoprecipitation
Arsenic trioxide
Molecular Biology
Polycomb Repressive Complex 1
biology
HEK 293 cells
Ubiquitination
Sumoylation
Oxides
Cell Biology
medicine.disease
Molecular biology
Gene Expression Regulation, Neoplastic
030104 developmental biology
HEK293 Cells
chemistry
Cell culture
030220 oncology & carcinogenesis
Proteolysis
Ubiquitin-Conjugating Enzymes
biology.protein
UBE2I
RNA Interference
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 00063002
- Volume :
- 1863
- Issue :
- 7 Pt
- Database :
- OpenAIRE
- Journal :
- Biochimica et biophysica acta
- Accession number :
- edsair.doi.dedup.....130ad60fda36d7056afcf40920824c2a