PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability

Silva, Ana; Yunes, José Andrés; Cardoso, Bruno; Martins, Leila R.; Jotta, Patricia Yoshioka; Abecasis, Miguel; Nowill, Alexandre E.; Leslie, Nicholas R.; Cardoso, Angelo A.; Barata, João T.

doi:10.1172/jci34616

Cited by 389 publications

(434 citation statements)

References 59 publications

(79 reference statements)

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“…Inhibition of CK2 restored PTEN activity and reduced PI3K/AKT activation, causing T-ALL cell death without affecting normal T-cell viability. 42 These data showed that PTEN could be inactivated by a protein kinase-mediated post-transcriptional, post-translational mechanism in ALL. In a follow-up work, the same group demonstrated the potential therapeutic efficacy of targeting CK2 with TBB in combination with the inhibition of Notch-dependent signaling through the use of gamma-secretase inhibitors, in T-ALL samples.…”

Section: Ck2 In Lymphoid Tumors Mouse Modelsmentioning

confidence: 93%

“…40,41 These initial reports implicating CK2 in lymphoid precursor tumors were followed by the demonstration that CK2 regulates the PI3K/AKT/ PTEN signaling cascade in T-ALL. Silva et al 42 showed that in primary T-ALL cells CK2 is overexpressed or hyperactivated. CK2-mediated phosphorylation of PTEN is known to result in its intracellular stabilization and---in parallel---in its functional inactivation.…”

Section: Ck2 In Lymphoid Tumors Mouse Modelsmentioning

confidence: 99%

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Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

et al. 2012

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CK2 is a multitask kinase whose role is essential for a countless number of cellular processes, many of which are critical for blood cell development. A prevailing task for this kinase rests on counteracting programmed cell death triggered by multiple stimuli. CK2 is overexpressed in many solid tumors and in vivo mouse models have proven its tumorigenic potential. Recent data have suggested that CK2 may also have a significant role in the pathogenesis of hematopoietic tumors, such as multiple myeloma, chronic lymphocytic leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia and chronic myeloproliferative neoplasms. CK2 regulates hematopoiesis-associated signaling pathways and seems to reinforce biochemical cascades indispensable for tumor growth, proliferation and resistance to conventional and novel cytotoxic agents. Although its activity is multifold, recent evidence supports the rationale of CK2 inhibition as a therapeutic strategy in solid and hematological tumors and phase-I clinical trials are in progress to test the efficacy of this innovative therapeutic approach. In this review, we will summarize the data supporting CK2 as an oncogenic kinase in blood tumors and we will describe some critical signaling pathways, whose regulation by this protein kinase may be implicated in tumorigenesis. Leukemia (2012Leukemia ( ) 26, 1174Leukemia ( --1179 doi:10.1038/leu.2011; published online 13 January 2012Keywords: hematopoiesis; blood tumors; protein kinase CK2; kinase inhibitors INTRODUCTION Protein kinase CK2 is a highly conserved pleiotropic acidophilic serine-threonine kinase whose essential role in several cellular processes has been increasingly appreciated over the last decade. 1 Structurally, CK2 is a tetrameric enzyme, composed by the assembly of two catalytic (a and/or a') and two regulatory b subunits. The catalytic and regulatory subunits may also be present in the cell as unassembled molecules and it seems that this state is associated with distinct and specific functions. The two catalytic subunits a and a' share 90% sequence homology in their N-terminal region. The regulatory subunit b instead does not have any similarity to the other two subunits. 2 CK2 recognizes motifs characterized by a S/T N-terminal to acidic amino acids, its minimum consensus being S/T-X-X-Ac, where X is any amino acid and Ac is a residue with a carboxylic or phosphorylated side chain (E, D, pS, pY).The spectrum of actions of this kinase is impressive as it can phosphorylate hundreds of substrate proteins, which are involved in disparate cellular processes, such as regulation of cell structure, division, proliferation, programmed death, DNA damage repair, protein translation, gene transcription, organelle function and so forth. 3 It has been estimated that a substantial proportion of the human phosphoproteome (up to 20%) is generated by CK2 alone. For this reason, CK2 has long been viewed as a 'non-targetable' kinase for therapeutic purposes.The essential role of CK2 for cell and organism life is underscored by th...

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Section: Ck2 In Lymphoid Tumors Mouse Modelsmentioning

confidence: 93%

Section: Ck2 In Lymphoid Tumors Mouse Modelsmentioning

confidence: 99%

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

et al. 2012

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“…PTEN oxidization has been proposed to contribute to the development of T-cell acute lymphoblastic leukemia (T-ALL), which displays abnormally high levels of ROS. 27,55 The peroxidase peroxiredoxin1 (Prdx1) gene product regulates PTEN in response to ROS. 56 In Prdx1-deficient mouse fibroblasts and mammary epithelial cells, Akt is hyperactive.…”

Section: Pseudo-pten and Other Oncogenes Decoys For Mirnasmentioning

confidence: 99%

“…21,22,25,26 Thus, PTEN is an enticing therapeutic target for activation as it is frequently inactivated in many human cancers through point mutations as well as other means (for example, promoter hypermethylation, gene deletion) and its inactivation results in elevated Akt activity and abnormal growth regulation. 21,22,27,28 Moreover, PTEN can be inactivated by phosphorylation and oxidation in human cancer and which results in elevated Akt activity and abnormal growth regulation. 29 Some cells become therapy resistant by inactivation of PTEN.…”

Section: Introductionmentioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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“…10 In addition, ROS can contribute to leukaemic cell transformation. 11 Bearing the foregoing in mind, it would be reasonable to assume that ROS production could have a direct role in haematopoietic differentiation. Nevertheless, there are almost no studies addressing this issue, with just one report describing the differentiation of a promonocytic cell line into macrophages.…”

mentioning

confidence: 99%

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

et al. 2010

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Transient reactive oxygen species (ROS) production is currently proving to be an important mechanism in the regulation of intracellular signalling, but reports showing the involvement of ROS in important biological processes, such as cell differentiation, are scarce. In this study, we show for the first time that ROS production is required for megakaryocytic differentiation in K562 and HEL cell lines and also in human CD34 þ cells. ROS production is transiently activated during megakaryocytic differentiation, and such production is abolished by the addition of different antioxidants (such as N-acetyl cysteine, trolox, quercetin) or the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium. The inhibition of ROS formation hinders differentiation. RNA interference experiments have shown that a p22 phoxdependent NADPH oxidase activity is responsible for ROS production. In addition, the activation of ERK, AKT and JAK2 is required for differentiation, but the activation of phosphatidylinositol 3-kinase and c-Jun N-terminal kinase seems to be less important. When ROS production is prevented, the activation of these signalling pathways is partly inhibited. Taken together, these results show that NADPH oxidase ROS production is essential for complete activation of the main signalling pathways involved in megakaryocytopoiesis to occur. We suggest that this might also be important for in vivo megakaryocytopoiesis.

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PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability

Cited by 389 publications

References 59 publications

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

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