Programmed cell death-4 tumor suppressor protein contributes to retinoic acid-induced terminal granulocytic differentiation human myeloid leukemia cells
ABSTRACT Programmed cell death-4 (PDCD4) is a recently discovered tumor suppressor protein that inhibits protein synthesis by suppression of translation initiation. We investigated the role and the regulation of PDCD4 in the terminal differentiation of acute myeloid leukemia (AML) cells. Expression of PDCD4 was markedly up-regulated during all-trans retinoic acid (ATRA)-induced granulocytic differentiation in NB4 and HL60 AML cell lines and in primary human promyelocytic leukemia (AML-M3) and CD34(+) hematopoietic progenitor cells but not in differentiation-resistant NB4.R1 and HL60R cells. Induction of PDCD4 expression was associated with nuclear translocation of PDCD4 in NB4 cells undergoing granulocytic differentiation but not in NB4.R1 cells. Other granulocytic differentiation inducers such as DMSO and arsenic trioxide also induced PDCD4 expression in NB4 cells. In contrast, PDCD4 was not up-regulated during monocytic/macrophagic differentiation induced by 1,25-dihydroxyvitamin D3 or 12-O-tetradecanoyl-phorbol-13-acetate in NB4 cells or by ATRA in THP1 myelomonoblastic cells. Knockdown of PDCD4 by RNA interference (siRNA) inhibited ATRA-induced granulocytic differentiation and reduced expression of key proteins known to be regulated by ATRA, including p27(Kip1) and DAP5/p97, and induced c-myc and Wilms' tumor 1, but did not alter expression of c-jun, p21(Waf1/Cip1), and tissue transglutaminase (TG2). Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway was found to regulate PDCD4 expression because inhibition of PI3K by LY294002 and wortmannin or of mTOR by rapamycin induced PDCD4 protein and mRNA expression. In conclusion, our data suggest that PDCD4 expression contributes to ATRA-induced granulocytic but not monocytic/macrophagic differentiation. The PI3K/Akt/mTOR pathway constitutively represses PDCD4 expression in AML, and ATRA induces PDCD4 through inhibition of this pathway.
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ABSTRACT: Acute promyelocytic leukemia (APL), the M3 subtype of acute myeloid leukemia, is one of the most successful examples of translational research in medicine, since the coordinated combination of laboratory and clinical stud-ies has transformed this leukemia from a fatal into a curable disease. In particular, the introduction of all-trans retinoic acid (ATRA) in APL therapy opened a new page in the history of tumor treatment, since this ago-nist is capable of inducing morphologic and functional maturation of APL blasts. In both APL blasts and APL-derived cell lines, ATRA-induced progression of promye-locytes to a more mature state is mediated through a complex regulation of gene transcription. The events mediated by proteins codified by ATRA target genes that account for the complex and integrated network of intra-cellular signaling pathways responsible of the comple-tion of maturation, are still largely unknown. In the last few years, the application of siRNA procedures to the study of molecular mechanisms that lead tumoral myeloid precursors to maturate along the granulocytic lineage has permitted to establish the specific role of a number of intracellular signaling molecules in a wide range of cell functions, including cell cycle regulation and control of gene expression. In particular, for some of these, as PLC-β β2 and Vav1, it was established a role in promoting maturation of APL-derived promyelocytes and in regulating the modifications of the cytoskeleton architecture that accompany maturation related motil-ity and migration. The identification of molecules that play crucial roles in the differentiation of APL cells will, ultimately, allow recognizing new possible targets for future therapies of APL patients. A cute Promyelocytic Leukemia (APL), the M3 sub-type of acute myeloid leukemia according to the French-American-British (FAB) classification, is char-acterized by a maturation block of myeloid precursors leading to an accumulation of abnormal heavily gran-ulated promyelocytes in peripheral blood and bone marrow. 1 The genetic hallmark of more than 95% of APL patients is the balanced reciprocal translocation t(15;17)(q22;q21), involving the genes encoding for the retinoic acid receptor-α (RARα) and for the promye-locytic leukemia protein (PML) and resulting in expres-sion of the chimerical protein PML/RARα. 1 RARα, a member of the retinoic acid nuclear receptors family, acts as a ligand-inducible transcription factor by bind-ing to specific response elements (RAREs) at the pro-Fundings. This research was supported by grants from MIUR Cofin (2005), Interdisciplinary Center for the Study of Inflammation (ICSI) and local founds from University of Ferrara (Italy) to S. Capitani and V. Bertagnolo.
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ABSTRACT: Vascular smooth muscle cells (VSMCs) are involved in all stages of the progression of human atherosclerosis (AS). MicroRNAs (miRNAs or miRs) are non‑coding, small RNAs that regulate gene expression at the post‑transcriptional level through translational repression or messenger RNA (mRNA) decay. Recently, a variety of functions of VSMCs that are involved in AS, including differentiation, migration, proliferation, extracellular matrix (ECM) synthesis and apoptosis, have been found to be regulated by miRNAs. This review provides an overview of the role of miRNAs in the regulation of the functions of VSMCs, as well as their targets and potential implications in AS. The data presented herein suggest that the specific modulation of miRNAs may present an attractive approach for the diagnosis and treatment of AS.International Journal of Molecular Medicine 07/2014; 34(4). DOI:10.3892/ijmm.2014.1853 · 1.88 Impact Factor
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ABSTRACT: Increased activity of PI3K/AKT/mTOR pathway has been observed in a huge number of malignancies. This pathway can function as a prosurvival factor in leukemia stem cells and early committed leukemic precursors and its inhibition is regarded as a therapeutic approach. Accordingly, the aim of this review is to evaluate the PI3K/Akt/mTOR inhibitors used in leukemia models. Inhibition of the PI3K/AKT/mTOR pathway has been reported to have beneficial therapeutic effects in leukemias, both in vitro in leukemia cell lines and in vivo in animal models. Overall, the use of dual PI3K/mTOR inhibitor, dual Akt/RTK inhibitor, Akt inhibitor, selective inhibitor of PI3K, mTOR inhibitor and dual PI3K/PDK1 inhibitor in CML, AML, APL, CLL, B-ALL and T-ALL has a better therapeutic effect than conventional treatments. Targeting the PI3K/Akt/mTOR pathway may have pro-apoptotic and antiproliferative effects on hematological malignancies. Furthermore, modulation of miRNA can be used as a novel therapeutic approach to regulate the PI3K/Akt/mTOR pathway. However, both aspects require further clinical studies.Cellular and Molecular Life Sciences CMLS 02/2015; DOI:10.1007/s00018-015-1867-5 · 5.86 Impact Factor