Pim serine/threonine kinases regulate the stability of Socs-1 protein

Chen, X. Peter; Losman, Julie A.; Cowan, Simone; Donahue, Elizabeth H.; Fay, Scott; Vuong, Bao Q.; Nawijn, Martijn C.; Capece, Danielle; Cohan, V. L.; Rothman, Paul B.

doi:10.1073/pnas.042035699

Cited by 167 publications

(174 citation statements)

References 31 publications

(34 reference statements)

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“…Our data raise the possibility that Cul5 dysregulation may play a role in the overexpression of Hsp90 client proteins in certain tumors. Interestingly, Cul5 expression has been shown to be decreased in a number of cancers, suggesting that Cul5 suppression may be beneficial for tumor development or maintenance (35). Our data also suggest that Cul5 can influence the effectiveness of anticancer treatment with GA or its derivatives, and its potential effects should be considered when evaluating the clinical efficacy of these treatments.…”

Section: Discussionmentioning

confidence: 80%

Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase

Ehrlich

Wang

Luo

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

108

106

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We report a link between Cullin5 (Cul5) E3 ubiquitin ligase and the heat shock protein 90 (Hsp90) chaperone complex. Hsp90 participates in the folding of its client proteins into their functional conformation. Many Hsp90 clients have been reported to be aberrantly expressed in a number of cancers. We demonstrate Cul5 interaction with members of the Hsp90 chaperone complex as well as the Hsp90 client, ErbB2. We observed recruitment of Cul5 to the site of ErbB2 at the plasma membrane and subsequent induction of polyubiquitination and proteasomal degradation. We also demonstrate Cul5 involvement in regulation of another Hsp90 client, Hif-1␣. We observed Cul5 degradation of ErbB2 to occur independently of ElonginB-ElonginC function. The involvement of Cul5 in Hsp90 client regulation has implications in the effectiveness of Hsp90 targeted chemotherapy, which is currently undergoing clinical trials. The link between Cul5 and Hsp90 client regulation may represent an avenue for cancer drug development.chaperone ͉ erbb2

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Section: Discussionmentioning

confidence: 80%

Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase

Ehrlich

Wang

Luo

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

108

106

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“…Interestingly, previous studies have shown that Pim-1 stabilizes SOCS-1 by phosphorylation. 32 Meanwhile, this study showed that Pim-1 also phosphorylates RelA/p65 at Ser276 to prevent from SOCS-1-mediated ubiquitination. We do not have any rationale to connect these distinct roles of Pim-1.…”

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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“…HSP40 and Pim 1 kinase up-regulation in early progenitors of CD8 cells is quenched in association with engagement of class I, whereas expression of Pim 1 kinase͞HSP40 persists in CD4 SP cells. IL-7R-based up-regulation of Pim1 kinase in early selection intermediates may allow post-transcriptional stabilization of SOCS-1 (44)(45)(46)(47), leading to diminished expression of IFN-␥ and other potentially lethal cytokines in neonatal life.…”

Section: Discussionmentioning

confidence: 99%

Detailed analysis of gene expression during development of T cell lineages in the thymus

McCarty

Shinohara

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The genetic mechanisms that promote lineage commitment and eliminate autoreactive cells in the thymus are not well understood. To better understand this process, we have identified and quantitated transcripts in the two major thymocyte lineages by using serial analysis of gene expression. Approximately 25 genes displayed almost complete segregation to one or the other T cell lineage. Commitment to the CD4 lineage was marked by upregulation of genes associated with increased survival and chaperone function followed by expression of genes that regulate nucleosome remodeling and T cell receptor signaling. Differentiation within the CD8 lineage, on the other hand, was marked by up-regulation of genes that regulate lymphocyte homing, followed by quenching of genes that inhibit apoptosis. Definition of differential gene expression during development of the two major thymocyte lineages will allow insight into mechanisms of T cell development after positive and negative selection.serial analysis of gene expression ͉ genetic profiling ͉ CD4͞CD8 ͉ lineage commitment T he two major T cell lineages that regulate adaptive immunity are generated and purged of clones bearing autoreactive T cell receptors (TCR) in the thymus (1). Although the molecular basis of TCR expression on thymocytes and T cells is relatively well understood, the mechanisms that orchestrate development and selection of TCR-bearing thymocytes have not been clearly defined. Delineation of the expression and potential function of genes expressed during the development of each lineage represents an important step in understanding this process.Thymocyte differentiation begins with migration of common lymphoid progenitor cells from hematopoietic stem cells in adult bone marrow or fetal liver into the thymus, where they undergo cellular maturation and TCR-based selection. Distinct developmental compartments have been defined according to expression of the CD4 and CD8 coreceptors on differentiating thymocytes. The earliest compartment is composed of CD4 Ϫ 8 Ϫ double negative (DN) thymocytes, which give rise to CD4 ϩ CD8 ϩ double positive (DP) intermediates, which yield mature CD4 ϩ CD8 Ϫ (CD4) or CD4 Ϫ CD8 ϩ (CD8) single positive (SP) mature progeny. The DN stage of thymocyte differentiation is marked by genetic events that prepare cells for TCR-based selection by self-MHC, including expression of recombination activating genes (RAG-1 and RAG-2) and initiation of TCR␤ gene rearrangements. These genetic events can be demarcated according to surface markers expressed sequentially on DN thymocytes (stages DN1-DN4) in order of their appearance during development (2, 3). DN1 and DN2 thymocytes proliferate before RAG-1͞-2 expression (4, 5), whereas the DN3 3 DN4 developmental step is accompanied by expression of a pre-TCR that inhibits further RAG-1͞-2 activity and promotes a second proliferative burst of cells that express both CD4 and CD8, marking transition into the DP compartment (6).Thymocytes that express the DP phenotype (by far the most abundant in the thymus) ...

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Pim serine/threonine kinases regulate the stability of Socs-1 protein

Cited by 167 publications

References 31 publications

Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase

Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase

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

Detailed analysis of gene expression during development of T cell lineages in the thymus

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