The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein
| Autor: | Hsiaoyin Mao, Mario Notari, Ashwin Uttam, Rebecca Bruner-Klisovic, Shujun Liu, Clara D. Bloomfield, Mauro Valtieri, Michael A. Caligiuri, Danilo Perrotti, Rossana Trotta, Ji Suk Chang, Denis C. Roy, Ramasamy Santhanam, Bradley W. Blaser, Paolo Neviani, Annamaria Galietta, Guido Marcucci |
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| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
Chromosomal Proteins Non-Histone Fusion Proteins bcr-abl Antineoplastic Agents Mice SCID In Vitro Techniques Piperazines Mice 03 medical and health sciences 0302 clinical medicine Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases Phosphoprotein Phosphatases Tumor Cells Cultured medicine Animals Humans Histone Chaperones Protein Phosphatase 2 Enzyme Inhibitors Kinase activity neoplasms Cell Line Transformed 030304 developmental biology 0303 health sciences Leukemia ABL Chemistry Cell growth Tumor Suppressor Proteins Colforsin breakpoint cluster region Cell Biology Protein phosphatase 2 medicine.disease DNA-Binding Proteins Pyrimidines Imatinib mesylate Oncology 030220 oncology & carcinogenesis Benzamides Imatinib Mesylate Cancer research Blast Crisis K562 Cells Neoplasm Transplantation Transcription Factors Chronic myelogenous leukemia K562 cells |
| Zdroj: | Cancer Cell. 8:355-368 |
| ISSN: | 1535-6108 |
| DOI: | 10.1016/j.ccr.2005.10.015 |
| Popis: | SummaryThe oncogenic BCR/ABL kinase activity induces and maintains chronic myelogenous leukemia (CML). We show here that, in BCR/ABL-transformed cells and CML blast crisis (CML-BC) progenitors, the phosphatase activity of the tumor suppressor PP2A is inhibited by the BCR/ABL-induced expression of the PP2A inhibitor SET. In imatinib-sensitive and -resistant (T315I included) BCR/ABL+ cell lines and CML-BC progenitors, molecular and/or pharmacological activation of PP2A promotes dephosphorylation of key regulators of cell proliferation and survival, suppresses BCR/ABL activity, and induces BCR/ABL degradation. Furthermore, PP2A activation results in growth suppression, enhanced apoptosis, restored differentiation, impaired clonogenic potential, and decreased in vivo leukemogenesis of imatinib-sensitive and -resistant BCR/ABL+ cells. Thus, functional inactivation of PP2A is essential for BCR/ABL leukemogenesis and, perhaps, required for blastic transformation. |
| Databáze: | OpenAIRE |
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