Elevated Levels of Oncogenic Protein Kinase Pim-1 Induce the p53 Pathway in Cultured Cells and Correlate with Increased Mdm2 in Mantle Cell Lymphoma

Hogan, Carol; Hutchison, Caroline; Marcar, Lynnette; Milne, Diane; Saville, Mark K.; Goodlad, John; Kernohan, Neil M.; Meek, David W.

doi:10.1074/jbc.m709695200

Cited by 74 publications

(72 citation statements)

References 55 publications

(113 reference statements)

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“…We further showed that this decrease in miR-1 expression is associated with an increase in oncogenic MET, Pim-1, FoxP1, and HDAC4. Pim-1 is a Ser/Thr kinase overexpressed in various human cancers and plays a causal role in lymphoma and leukemogenesis (50,51). Our study shows that it is also up-regulated in the majority of human primary lung tumors and cancer cell lines.…”

Section: Discussionmentioning

confidence: 57%

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Down-regulation of Micro-RNA-1 (miR-1) in Lung Cancer: Suppression of Tumorigenic Property of Lung Cancer Cells and Their Sensitization to Doxorubicin-Induced Apoptosis by miR-1

Nasser

Datta

Nuovo

et al. 2008

Journal of Biological Chemistry

325

139

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Lung cancer is the leading cause of cancer-related deaths both in men and women in the United States, with an incidence of ϳ213,000 new cases/year (1). Approximately 80% of lung cancers are classified histopathologically as non-small cell lung cancers. At early stages of non-small cell lung cancer, the only treatment is surgery, with a 5-year overall survival rate of 40% (2), whereas chemotherapy is mostly employed for small cell lung cancer. The majority of patients have developed an aggressive form of the disease by the time of diagnosis, limiting the scope for therapeutic intervention. At this stage, several genetic and epigenetic changes take place, resulting in epithelial cell hyperplasia and, eventually, dysplasia. These changes are attributed to silencing of tumor suppressor genes, dysregulation of proto-oncogenes, and an up-regulation of genes that promote cell growth and transformation and ultimately tumor development (3).

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Section: Discussionmentioning

confidence: 57%

“…Oncogenic Ser/Thr Kinase Pim-1, a Target of miR-1, Is Significantly Up-regulated in Lung CancerPim-1, a Ser/Thr kinase, induces tumorigenesis by promoting cell cycle progression and inhibiting apoptosis (50,51). Since its 3Ј-UTR harbors one miR-1 cognate site (Fig.…”

Section: Foxp1 and Hdac4 Targets Of Mir-1 Are Also Differentially Rmentioning

confidence: 99%

Down-regulation of Micro-RNA-1 (miR-1) in Lung Cancer: Suppression of Tumorigenic Property of Lung Cancer Cells and Their Sensitization to Doxorubicin-Induced Apoptosis by miR-1

Nasser

Datta

Nuovo

et al. 2008

Journal of Biological Chemistry

325

139

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“…PIM1 associated with and phosphorylated Mdm2 at Ser166 and Ser186 leading to stabilization of both proteins. 66 More work is needed to validate the impact of PIM-mediated p53 regulation for induction and/or maintenance of malignant transformation.…”

Section: Pim2mentioning

confidence: 99%

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Brault¹,

Gasser²,

Bracher³

et al. 2010

Haematologica

327

413

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The online version of this article has a Supplementary Appendix.The identification as cooperating targets of Proviral Integrations of Moloney virus in murine lymphomas suggested early on that PIM serine/threonine kinases play an important role in cancer biology. Whereas elevated levels of PIM1 and PIM2 were mostly found in hematologic malignancies and prostate cancer, increased PIM3 expression was observed in different solid tumors. PIM kinases are constitutively active and their activity supports in vitro and in vivo tumor cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators. PIM1 but not PIM2 seems also to mediate homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that PIM kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets. Determination of the protein structure facilitated identification of an increasing number of potent small molecule PIM kinase inhibitors with in vitro and in vivo anticancer activity. Ongoing efforts aim to identify isoform-specific PIM inhibitors that would not only help to dissect the kinase function but hopefully also provide targeted therapeutics. Here, we summarize the current knowledge about the role of PIM serine/threonine kinases for the pathogenesis and therapy of hematologic malignancies and solid cancers, and we highlight structural principles and recent progress on small molecule PIM kinase inhibitors that are on their way into first clinical trials. Haematologica 2010;95:1004-1015. doi:10.3324/haematol.2009 This is an open-access paper. ABSTRACTin blast crisis. 6 Abundant levels of PIM1 were found in hematopoietic cells. Moreover, sustained PIM1 expression was induced by cytokines that signal through structurally related receptors such as IL-3, GM-CSF, G-CSF or Subsequently, several studies have documented that PIM1 is a major downstream target of the signal transducer and activator of transcription (STATs) induced by a large variety of additional receptors such as IL-2, IL-7, IL-9, IFNγ, EPO, FLT3 or TPO.7 PIM1 expression is not only regulated at the transcriptional, but also at the posttranscriptional, translational and posttranslational levels ( Figure 1). Other studies have shown that PIM1 kinase is significantly protected from proteasomal degradation by heat shock proteins (Hsp70, Hsp90). 8,9 Moreover, it has been proposed that micro-RNAs, miR-1 and miR-210, might be implicated in regulation of PIM1 expression. 10,11 Germline inactivation of the PIM1 gene was associated with a mild phenotype as PIM1 deficient mice are ostensibly normal, healthy and fertile. However, subtle functional defects of the hematopoietic system have been identified: PIM1 -/-mice showed erythrocytic microcytosis and PIM1-/-B cells and bone marrow-derived mast c...

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“…12 In addition, elevated Pim-1 expression in MCL has been reported to induce the p53 pathway and correlate with increased expression of MDM2. 13 Furthermore, Pim-1 expression is known to be highly associated with poor outcome in MCL patients. 7 These observations suggest that Pim kinases could be potential therapeutic targets in MCL.…”

Section: Introductionmentioning

confidence: 99%

Transcription and translation are primary targets of Pim kinase inhibitor SGI-1776 in mantle cell lymphoma

Yang

Chen

Neelapu³

et al. 2012

Blood

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IntroductionMantle cell lymphoma (MCL) is an aggressive lymphoma characterized by overexpression of cyclin D1 caused by t(11:14)(q13; q32). 1 Although current therapeutic approaches provide a good response rate (Ͼ 90%) and progression-free survival (ϳ 2.5 years), there is no effective cure for this disease. 2,3 Hence, identification of novel targets and their inhibition are needed in MCL.Proviral integration site for Moloney murine leukemia virus (Pim) kinases are oncoproteins that promote tumor progression. 4 To date, 3 Pim kinases have been identified. Pim-1, -2, and -3 are highly conserved serine/threonine/tyrosine kinases that are important for normal B-lymphocyte development 5 and that are overexpressed in B-cell malignancies, such as chronic lymphocytic leukemia (CLL) 6 and MCL. [7][8][9] In addition, Pim-1 and Pim-2 have been found to be highly expressed in other hematologic malignancies 10 as well as in solid tumors, such as prostate cancer. 11 c-Myc, also a Pim kinase substrate, has been observed to coexpress with Pim kinase in B-cell malignancies. 12 In addition, elevated Pim-1 expression in MCL has been reported to induce the p53 pathway and correlate with increased expression of MDM2. 13 Furthermore, Pim-1 expression is known to be highly associated with poor outcome in MCL patients. 7 These observations suggest that Pim kinases could be potential therapeutic targets in MCL.Pim kinase genes are early responders to growth factors and cytokines. 14 These kinases are highly conserved throughout evolution, yet Pim-1, -2, and -3 triple-knockout mice are viable and fertile, revealing the dispensability of these proteins in crucial physiologic developmental processes. 5 Pim kinases phosphorylate several substrates, including c-Myc and Histone H3 (H3) that drive the transcription process. 12,15 Pim-1 phosphorylation of Histone H3 at Ser10 has been reported to be a necessary event for c-Mycdriven transcription. 15 Pim-1 phosphorylates c-Myc at Ser62 to stabilize this protein. 16 Notably, both Pim-1 and Pim-2 work synergistically with c-Myc, as confirmed by double-knockout studies in mice. 5 The translation regulator eukaryotic elongation factor 4E-BP1 is also a substrate of Pim kinases. Pim kinases phosphorylate the priming sites Thr37/46, allowing for the hyperphosphorylation of 4E-BP1, including Ser65 phosphorylation by Pim-2, causing it to dissociate from eukaryotic initiation factor 4. 17,18 Dissociation of eukaryotic initiation factor 4 contributes to the activation of cap-dependent translation. 18,19 In addition, Pim-1 and Pim-2 phosphorylate Bcl-2-associated death promoter (Bad) at Ser112; this phosphorylation disrupts binding of Bad to the antiapoptotic protein B-cell lymphoma-extra large (Bcl-X L ) and allows Bad to bind scaffold protein 14-3-3 to sequester its proapoptotic function, thereby activating a cell survival pathway. 20,21 Furthermore, cell cycle proteins such as CDKN1B (or p27) and cell division cycle 25A/C are phosphorylated by Pim kinases and are involved in promoting proliferation. [22]...

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Elevated Levels of Oncogenic Protein Kinase Pim-1 Induce the p53 Pathway in Cultured Cells and Correlate with Increased Mdm2 in Mantle Cell Lymphoma

Cited by 74 publications

References 55 publications

Down-regulation of Micro-RNA-1 (miR-1) in Lung Cancer: Suppression of Tumorigenic Property of Lung Cancer Cells and Their Sensitization to Doxorubicin-Induced Apoptosis by miR-1

Down-regulation of Micro-RNA-1 (miR-1) in Lung Cancer: Suppression of Tumorigenic Property of Lung Cancer Cells and Their Sensitization to Doxorubicin-Induced Apoptosis by miR-1

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Transcription and translation are primary targets of Pim kinase inhibitor SGI-1776 in mantle cell lymphoma

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