For better or for worse: the role of Pim oncogenes in tumorigenesis

Nawijn, Martijn C.; Alendar, Andrej; Berns, Anton

doi:10.1038/nrc2986

Cited by 428 publications

(461 citation statements)

References 165 publications

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“…Moreover, Pim-2 overexpression in HCT116 cells leads to enhanced phosphorylation of p21 to increase its stability (41). Furthermore, Pim-3 can augment protein synthesis (13) and regulate transcriptional activity of Myc (30). However, overexpression or ablation of Pim-3 failed to induce any changes in TCTP protein expression or phospho-TCTP ser46 levels.…”

Section: Discussionmentioning

confidence: 92%

“…As Pim kinases do not possess a regulatory domain and are constitutively active when they are expressed (28), the activity of Pim kinases is largely regulated at transcriptional, translation, and posttranslational levels (29). Furthermore, a very short half-life of their mRNA and protein (30) suggests the importance of regulation of Pim kinase protein levels.…”

Section: Discussionmentioning

confidence: 99%

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A Novel Regulatory Mechanism of Pim-3 Kinase Stability and Its Involvement in Pancreatic Cancer Progression

Zhang

Liu

Wang

et al. 2013

Molecular Cancer Research

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Translationally controlled tumor protein (TCTP/TPT1) was identified from a yeast 2-hybrid screen and shown to interact with Pim-3, a member of the proto-oncogene Pim family with serine/threonine kinase activity. TCTP was aberrantly expressed in human pancreatic cancer cells and malignant ductal epithelial cells, but not in normal pancreatic duct epithelial cells adjacent to tumor foci of human pancreatic cancer tissue. Moreover, TCTP colocalized with Pim-3 both in human pancreatic cancer cells and in clinical tissues. Mapping studies revealed that the interaction between Pim-3 and TCTP occurred through the C-terminal region of Pim-3 and N-terminal region of TCTP. Although Pim-3 had no effect on TCTP expression or phosphorylation, overexpression of TCTP increased the amount of Pim-3 in a dose-dependent manner. Interestingly, RNAi-mediated ablation of TCTP expression reduced Pim-3 protein but not mRNA, through a mechanism involving the ubiquitin-proteasome degradation system. As a consequence of Pim-3 instability and subsequent degradation, tumor growth in vitro and in vivo was inhibited by arresting cell-cycle progression and enhancing apoptosis. Furthermore, TCTP and Pim-3 expression were significantly correlated in pancreatic adenocarcinoma specimens, and patients with highly expressed TCTP and Pim-3 presented with a more advanced tumor stage. These observations indicate that TCTP enhances Pim-3 stability to simultaneously promote and prevent cell-cycle progression and apoptosis, respectively. Hence, TCTP and Pim-3 serve a pivotal role in human pancreatic cancer with important ramifications for clinical diagnostic and therapeutic implications.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

A Novel Regulatory Mechanism of Pim-3 Kinase Stability and Its Involvement in Pancreatic Cancer Progression

Zhang

Liu

Wang

et al. 2013

Molecular Cancer Research

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“…PIM oncogenes are frequently overexpressed in human hematological malignancies and in several solid tumors, for example in prostate and breast cancer. PIM kinases exert their oncogenic potential through regulating MYC transcriptional activity, cap-dependent protein translation, cellcycle progression as well as through suppression of apoptosis by means of BCL2-associated agonist of cell death (Bad) phosphorylation (for review, see Brault et al, 2010;Nawijn et al, 2011). Isoforms of Pim kinases include Pim-1, -2 and -3 (each B33 kDa), and utilization of alternative start codons gives rise to additional size variants, that is, 44 kDa (Pim-1; Xie et al, 2006) or 37 and 40 kDa (Pim-2;Fox et al, 2003), respectively (Amaravadi and Thompson, 2005).…”

Section: Introductionmentioning

confidence: 99%

The proto-oncogene Pim-1 is a target of miR-33a

et al. 2011

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The constitutively active serine/threonine kinase Pim-1 is upregulated in different cancer types, mainly based on the action of several interleukines and growth factors at the transcriptional level. So far, a regulation of oncogenic Pim-1 by microRNAs (miRNAs) has not been reported. Here, we newly establish miR-33a as a miRNA with potential tumor suppressor activity, acting through inhibition of Pim-1. A screen for miRNA expression in K562 lymphoma, LS174T colon carcinoma and several other cell lines revealed generally low endogenous miR33a levels relative to other miRNAs. Transfection of K562 and LS174T cells with a miR-33a mimic reduced Pim-1 levels substantially. In contrast, the cell-cycle regulator cyclin-dependent kinase 6 predicted to be a conserved miR-33a target, was not downregulated by the miR-33a mimic. Seed mutagenesis of the Pim-1 3 0 -untranslated region in a luciferase reporter construct and in a Pim-1 cDNA expressed in Pim-1-deficient Skov-3 cells demonstrated specific and direct downregulation of Pim-1 by the miR-33a mimic. The persistence of this effect was comparable to that of a small interfering RNA-mediated knockdown of Pim-1, resulting in decelerated cell proliferation. In conclusion, we demonstrate the potential of miR-33a to act as a tumor suppressor miRNA, which suggests miR-33a replacement therapy through delivery of miR mimics as a novel therapeutic strategy.

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“…They affect tumor cell proliferation and survival through multiple mechanisms that include inhibition of major signaling pathways, interference with the activity of specific cell cycle molecules, and changes in gene expression 117 . Overexpression of Pim kinases has been observed in patients with non-Hodgkin's lymphoma, leukemia, and prostate cancer [118][119][120][121] .The up-regulation of Pim kinases by hypoxia appears to be limited to Pim-1 (ref.…”

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confidence: 99%

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

et al. 2015

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Background. The aim of this review is to provide the information about molecular basis of hypoxia-induced chemoresistance, focusing on the possibility of diagnostic and therapeutic use. Results. Hypoxia is a common feature of tumors and represents an independent prognostic factor in many cancers. It is the result of imbalances in the intake and consumption of oxygen caused by abnormal vessels in the tumor and the rapid proliferation of cancer cells. Hypoxia-induced resistance to cisplatin, doxorubicin, etoposide, melphalan, 5-flouoruracil, gemcitabine, and docetaxel has been reported in a number of experiments. Adaptation of tumor cells to hypoxia has important biological effects. The most studied factor responsible for these effects is hypoxia-inducible factor-1 (HIF-1) that significantly contributes to the aggressiveness and chemoresistance of different tumors. The HIF-1 complex, induced by hypoxia, binds to target genes, thereby increasing the expression of many genes. In addition, the expression of hundreds of genes can be also decreased in response to hypoxia in HIF-1 dependent manner, but without the detection of HIF-1 in these genes' promoters. HIF-1 independent mechanisms for drug resistance in hypoxia have been described, however, they are still rarely reported. The first clinical studies focusing on diagnosis of hypoxia and on inhibition of hypoxia-induced changes in cancer cells are starting to yield results. Conclusions. The adaptation to hypoxia requires many genetic and biochemical responses that regulate one another. Hypoxia-induced resistance is a very complex field and we still know very little about it. Different approaches to circumvent hypoxia in tumors are under development.

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For better or for worse: the role of Pim oncogenes in tumorigenesis

Cited by 428 publications

References 165 publications

A Novel Regulatory Mechanism of Pim-3 Kinase Stability and Its Involvement in Pancreatic Cancer Progression

A Novel Regulatory Mechanism of Pim-3 Kinase Stability and Its Involvement in Pancreatic Cancer Progression

The proto-oncogene Pim-1 is a target of miR-33a

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

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