Cancer cell, 2017-05, Vol.31 (5), p.697-710.e7
2017
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- Autor(en) / Beteiligte
- Titel
- TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated Senescence
- Ist Teil von
- Cancer cell, 2017-05, Vol.31 (5), p.697-710.e7
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARα, which antagonizes myeloid differentiation and promotes APL-initiating cell self-renewal. Combined all-trans retinoic acid (ATRA) with arsenic trioxide (As2O3) or chemotherapy dramatically improves the prognosis of APL patients. Here we report that expression of pseudokinase Tribble 3 (TRIB3) associates positively with APL progression and therapeutic resistance. The elevated TRIB3 expression promotes APL by interacting with PML-RARα and suppressing its sumoylation, ubiquitylation, and degradation. This represses PML nuclear body assembly, p53-mediated senescence, and cell differentiation, and supports cellular self-renewal. Genetically inhibiting TRIB3 expression or combination of a peptide disturbing TRIB3/PML-RARα interaction with ATRA/As2O3 eradicates APL by accelerating PML-RARα degradation. Our study provides insight into APL pathogenesis and a potential therapeutic option against APL. [Display omitted] •High TRIB3 expression promotes APL progression and resistance to therapy•TRIB3 inhibits PML-NBs, senescence, and differentiation but supports cell renewal•TRIB3/PML-RARα interaction inhibits PML-RARα sumoylation and degradation•Disturbing this interaction in cooperation with ATRA or As2O3 eradicates APL Li et al. find that TRIB3 promotes acute promyelocytic leukemia (APL) by suppressing PML-RARα degradation and that the TRIB3 level correlates with APL progression and therapeutic resistance. Disrupting the TRIB3/PML-RARα interaction with a peptide in combination with ATRA or As2O3 suppresses APL in vivo.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-6108eISSN: 1878-3686DOI: 10.1016/j.ccell.2017.04.006Titel-ID: cdi_proquest_miscellaneous_1905678279
- Format
- –
- Schlagworte
- AML, Animals, Antineoplastic Combined Chemotherapy Protocols - pharmacology, Arsenicals - pharmacology, Cell Cycle Proteins - deficiency, Cell Cycle Proteins - genetics, Cell Cycle Proteins - metabolism, cell differentiation, Cell Differentiation - drug effects, Cell Line, Tumor, Cell Proliferation, Cellular Senescence, Disease Progression, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Gene Fusion, HEK293 Cells, Humans, Leukemia, Promyelocytic, Acute - drug therapy, Leukemia, Promyelocytic, Acute - genetics, Leukemia, Promyelocytic, Acute - metabolism, Leukemia, Promyelocytic, Acute - pathology, leukemia-initiating cells, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Oncogene Proteins, Fusion - genetics, Oncogene Proteins, Fusion - metabolism, Oxides - pharmacology, Peptides - pharmacology, protein quality control, Protein Stability, protein-protein interaction, Protein-Serine-Threonine Kinases - antagonists & inhibitors, Protein-Serine-Threonine Kinases - genetics, Protein-Serine-Threonine Kinases - metabolism, Proteolysis, psuedokinase, Repressor Proteins - genetics, Repressor Proteins - metabolism, Signal Transduction, Sumoylation, Time Factors, Transfection, Tretinoin - pharmacology, tribbles, Tumor Suppressor Protein p53 - genetics, Tumor Suppressor Protein p53 - metabolism, Ubiquitination, UPS, Xenograft Model Antitumor Assays