Yan Y, Hanse E A, Stedman K, Benson J M, Lowman X H, Subramanian S, Kelekar A
Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
Cell Death Differ. 2016 Jul;23(7):1232-42. doi: 10.1038/cdd.2016.1. Epub 2016 Feb 12.
PHLPP2, a member of the PH-domain leucine-rich repeat protein phosphatase (PHLPP) family, which targets oncogenic kinases, has been actively investigated as a tumor suppressor in solid tumors. Little is known, however, regarding its regulation in hematological malignancies. We observed that PHLPP2 protein expression, but not its mRNA, was suppressed in late differentiation stage acute myeloid leukemia (AML) subtypes. MicroRNAs (miR or miRNAs) from the miR-17-92 cluster, oncomir-1, were shown to inhibit PHLPP2 expression and these miRNAs were highly expressed in AML cells that lacked PHLPP2 protein. Studies showed that miR-17-92 cluster regulation was, surprisingly, independent of transcription factors c-MYC and E2F in these cells; instead all-trans-retinoic acid (ATRA), a drug used for terminally differentiating AML subtypes, markedly suppressed miR-17-92 expression and increased PHLPP2 protein levels and phosphatase activity. Finally, we demonstrate that the effect of ATRA on miR-17-92 expression is mediated through its target, transcription factor C/EBPβ, which interacts with the intronic promoter of the miR-17-92 gene to inhibit transactivation of the cluster. These studies reveal a novel mechanism for upregulation of the phosphatase activity of PHLPP2 through C/EBPβ-mediated repression of the miR-17-92 cluster in terminally differentiating myeloid cells.
PHLPP2是PH结构域富含亮氨酸重复蛋白磷酸酶（PHLPP）家族的成员，该家族作用于致癌激酶，作为实体瘤中的肿瘤抑制因子已受到广泛研究。然而，关于其在血液系统恶性肿瘤中的调控机制却知之甚少。我们观察到，在急性髓系白血病（AML）晚期分化亚型中，PHLPP2蛋白表达受到抑制，但其mRNA表达未受影响。来自miR-17-92簇（致癌miR-1）的微小RNA（miR或miRNAs）可抑制PHLPP2表达，且这些miRNAs在缺乏PHLPP2蛋白的AML细胞中高表达。研究表明，令人惊讶的是，在这些细胞中miR-17-92簇的调控独立于转录因子c-MYC和E2F；相反，用于使AML亚型终末分化的药物全反式维甲酸（ATRA）可显著抑制miR-17-92表达，并增加PHLPP2蛋白水平和磷酸酶活性。最后，我们证明ATRA对miR-17-92表达的影响是通过其靶点转录因子C/EBPβ介导的，C/EBPβ与miR-17-92基因的内含子启动子相互作用，抑制该簇的反式激活。这些研究揭示了一种新机制，即在终末分化的髓系细胞中，通过C/EBPβ介导的对miR-17-92簇抑制来上调PHLPP2的磷酸酶活性。
