Crystal Structures of Proto-oncogene Kinase Pim1: A Target of Aberrant Somatic Hypermutations in Diffuse Large Cell Lymphoma

Kumar, Abhinav; Mandiyan, Valsan; Suzuki, Yoshihisa; Zhang, Chao; Rice, Julie; Tsai, James; Artis, Dean R.; Ibrahim, Prabha; Bremer, Ryan

doi:10.1016/j.jmb.2005.02.039

Cited by 152 publications

(154 citation statements)

References 44 publications

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“…24 Furthermore, accumulating studies have revealed that pim-1 gene is a target of aberrant somatic hypermutation in non-Hodgkin 0 s lymphoma and B-cell lymphoma, 25,26 and some of the mutations markedly increase an enzymatic activity of Pim-1. 27 Although the ability of Pim kinase to stimulate cell growth and inhibit apoptosis may contribute to the promotion of tumorigenesis, 20 aberrant Pim kinase activation may induce tumorigenesis. Thus, both NF-kB and Pim kinase are implicated in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Pim-1 controls NF-κB signalling by stabilizing RelA/p65

et al. 2009

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Post-translational modification and degradation of proteins by the ubiquitin-proteasome system are key regulatory mechanisms in cellular responses to various stimuli. The NF-jB signaling pathway is controlled by the ubiquitin-mediated proteolysis. RelA/p65, which is a main subunit of NF-jB, is ubiquitinated for degradation by SOCS-1, but the functional mechanism of its ubiquitination remains poorly understood. In this study we show that phosphorylation of RelA/p65 at Ser276 prevents its degradation by ubiquitin-mediated proteolysis. In contrast, impairment of Ser276 phosphorylation affects constitutive degradation of RelA/p65. Importantly, we identify Pim-1 as a further kinase responsible for the phosphorylation of RelA/p65 at Ser276. Depletion of Pim-1 hinders not only Ser276 phosphorylation but also transactivation of RelA/p65 target genes. We also show that Pim-1 contributes to recruitment of RelA/p65 to jB-elements to activate NF-jB signalling after TNF-a stimulation. In concert with these results, the knockdown of Pim-1 impairs IL-6 production and augments apoptosis by interfering RelA/p65 activation. These findings provide a model in which Pim-1 phosphorylation of RelA/p65 at Ser276 allows defense against ubiquitin-mediated degradation and whereby exerts activation of NF-jB signalling. NF-kB is an inducible transcription factor that controls the expression of a number of proteins involved in the regulation of cell survival and immune response. 1 It is a dimmer formed from a multisubset family consisting of RelA/p65, RelB, c-Rel, p105/p50 (NF-kB1), and p100/p52 (NF-kB2). It is activated by a bewildering array of stimuli and its activation is regulated by multiple distinct signalling cascades, including inhibitors of the NF-kB (IkB) kinase (IKK) signalosome. IKK phosphorylates IkB-a at Ser32 and Ser36 in response to a variety of stimuli, resulting in its ubiquitination and subsequent proteasomal degradation. The released NF-kB targets to the nucleus and thereby induces the expression of specific target genes. In addition to nuclear translocation of the NF-kB complex, previous studies have shown that a subunit of NF-kB, RelA/ p65, is post-translationally modified, such as phosphorylation, ubiquitination, or acetylation, and these changes influence its transcriptional activity. In particular, phosphorylation of RelA/ p65 at Ser276, Ser529, or Ser536 could be indispensable for its ability to function as an activator of gene expression. 2 However, recent findings showing a role for Ser529/536 phosphorylation on RelA/p65 activation in response to TNF-a arise conflicting evidences. [3][4][5] In contrast, accumulating evidences have revealed that Ser276 phosphorylation is critical for transactivation of RelA/p65 at least in response to TNF-a. Moreover, Ser276 is the major phosphorylation site of RelA/p65 induced by TNF-a. Phospho-RelA/p65 at Ser276 forms a stable complex with co-activator CBP/p300, a modification apparently required for assembly of a functional enhanceosome on the responsive promoters. 6,7 As nucle...

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Section: Discussionmentioning

confidence: 99%

Pim-1 controls NF-κB signalling by stabilizing RelA/p65

et al. 2009

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“…33,34 PIM1 is a serine/threonine kinase involved in several biological functions including cell survival, proliferation and differentiation. 35 PIM1 has been shown to be involved in several hematopoietic cancers, and has recently been identified as a target of aberrant somatic hypermutation in diffuse large B-cell lymphomas. 35,36 Epstein-Barr virus (EBV) has been shown to induce the upregulation of PIM kinases which is thought to contribute to the ability of EBV to immortalize B cells and predispose them to malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

“…35 PIM1 has been shown to be involved in several hematopoietic cancers, and has recently been identified as a target of aberrant somatic hypermutation in diffuse large B-cell lymphomas. 35,36 Epstein-Barr virus (EBV) has been shown to induce the upregulation of PIM kinases which is thought to contribute to the ability of EBV to immortalize B cells and predispose them to malignant transformation. 37 ErbB-3 is a 148 kDa type I membrane receptor tyrosine kinase protein.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive identification of proteins in Hodgkin lymphoma-derived Reed–Sternberg cells by LC-MS/MS

Wallentine

Kim

Seiler

et al. 2007

Laboratory Investigation

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Mass spectrometry-based proteomics in conjunction with liquid chromatography and bioinformatics analysis provides a highly sensitive and high-throughput approach for the identification of proteins. Hodgkin lymphoma is a form of malignant lymphoma characterized by the proliferation of Reed-Sternberg cells and background reactive lymphocytes. Comprehensive analysis of proteins expressed and released by Reed-Sternberg cells would assist in the discovery of potential biomarkers and improve our understanding of its pathogenesis. The subcellular proteome of the three cellular compartments from L428 and KMH2 Hodgkin lymphoma-derived cell lines were fractionated, and analyzed by reversephase liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Additionally, proteins released by Hodgkin lymphoma-derived L428 cells were extracted from serum-free culture media and analyzed. Peptide spectra were analyzed using TurboSEQUEST s against the UniProt protein database (5.26.05; 188 712 entries). A subset of the identified proteins was validated by Western blot analysis, immunofluorescence microscopy and immunohistochemistry. A total of 1945 proteins were identified with 785 from the cytosolic fraction, 305 from the membrane fraction, 441 from the nuclear fraction and 414 released proteins using a minimum of two peptide identifications per protein and an error rate of o5.0%. Identification of proteins from diverse functional groups reflected the functional complexity of the Reed-Sternberg proteome. Proteins with previously reported oncogenic function in other cancers and from signaling pathways implicated in Hodgkin lymphoma were identified. Selected proteins without previously demonstrated expression in Hodgkin lymphoma were validated by Western blot analysis (B-RAF, Erb-B3), immunofluorescence microscopy (Axin1, Tenascin-X, Mucin-2) and immunohistochemistry using a tissue microarray (BRAF, PIM1). This study represents the first comprehensive inventory of proteins expressed by Reed-Sternberg cells of Hodgkin lymphoma and demonstrates the utility of combining cellular subfractionation, protein precipitation, tandem mass spectrometry and bioinformatics analysis for comprehensive identification of proteins that may represent potential biomarkers of the disease.

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“…This Pro residue is unable to maintain a hydrogen bond network to the urea group of NSC 109555 because it lacks the amide hydrogen, but the inhibitor could potentially maintain the guanidinium-glutamate interaction. 35 Nevertheless, NSC 109555 was found to be poorly active against PIM-1 kinase (IC 50 >10 lM).…”

Section: Structural Insights Into Chk2 Selectivitymentioning

confidence: 99%

Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

et al. 2008

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Checkpoint kinase 2 (Chk2), a ser/thr kinase involved in the ATM-Chk2 checkpoint pathway, is activated by genomic instability and DNA damage and results in either arrest of the cell cycle to allow DNA repair to occur or apoptosis if the DNA damage is severe. Drugs that specifically target Chk2 could be beneficial when administered in combination with current DNAdamaging agents used in cancer therapy. Recently, a novel inhibitor of Chk2, NSC 109555, was identified that exhibited high potency (IC 50 = 240 nM) and selectivity. This compound represents a new chemotype and lead for the development of novel Chk2 inhibitors that could be used as therapeutic agents for the treatment of cancer. To facilitate the discovery of new analogs of NSC 109555 with even greater potency and selectivity, we have solved the crystal structure of this inhibitor in complex with the catalytic domain of Chk2. The structure confirms that the compound is an ATP-competitive inhibitor, as the electron density clearly reveals that it occupies the ATPbinding pocket. However, the mode of inhibition differs from that of the previously studied structure of Chk2 in complex with debromohymenialdisine, a compound that inhibits both Chk1 and Chk2. A unique hydrophobic pocket in Chk2, located very close to the bound inhibitor, presents an opportunity for the rational design of compounds with higher binding affinity and greater selectivity.

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Crystal Structures of Proto-oncogene Kinase Pim1: A Target of Aberrant Somatic Hypermutations in Diffuse Large Cell Lymphoma

Cited by 152 publications

References 44 publications

Pim-1 controls NF-κB signalling by stabilizing RelA/p65

Pim-1 controls NF-κB signalling by stabilizing RelA/p65

Comprehensive identification of proteins in Hodgkin lymphoma-derived Reed–Sternberg cells by LC-MS/MS

Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

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