High-Intensity p38 Kinase Activity Is Critical for p21cip1 Induction and the Antiproliferative Function of Gi Protein-Coupled Receptors

Alderton, Forbes; Humphrey, P. P. A.; Sellers, Lynda A.

doi:10.1124/mol.59.5.1119

Cited by 48 publications

(43 citation statements)

References 40 publications

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“…This might explain the opposite effects because growth inhibition by persistent signaling has been described for several G proteincoupled receptors. Examples are gonadotrophin-releasing hormone (GRHR), somatotrophin (sst2), and M3 muscarinic acetylcholine (29)(30)(31) receptors that cause persistent activation of the mitogenactivated protein kinases extracellular signal-regulated kinase 1/2, p38, and c-Jun NH 2 -terminal kinase, respectively. Whereas the growth-promoting M2 and sst3 receptors are rapidly degraded after internalization, the M3 and sst2 receptors are rapidly recycled to the surface (32,33), which is a likely explanation for the persistence of the signals.…”

Section: Discussionmentioning

confidence: 99%

The Chemokine Receptor CXCR6 and Its Ligand CXCL16 Are Expressed in Carcinomas and Inhibit Proliferation

Meijer¹,

Ogink²,

Kreike

et al. 2008

Cancer Research

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The chemokine receptor CXCR6 and its ligand CXCL16 are involved in inflammation. Thus far, they were known to be expressed mainly by T cells and macrophages, respectively. However, we detected both in all of 170 human primary mammary carcinomas and at similar levels in all 8 human mammary carcinoma cell lines tested by microarray analysis. Expression was confirmed by reverse transcription-PCR and for the cell lines also by fluorescence-activated cell sorting analysis. CXCR6 and CXCL16 were also detected in several mouse and human mammary, colon, and pancreatic carcinoma cell lines. CXCL16 is a transmembrane protein from which the soluble chemokine can be cleaved off. The transmembrane form is present on the surface of the carcinoma cells. Surprisingly, suppression of either CXCR6 or CXCL16 led to greatly enhanced proliferation in vitro as well as in vivo, indicating that their interaction inhibits proliferation. This notion was verified using inhibitory antibodies and by introduction of CXCL16 into a rare CXCL16-negative cell line. The effect was mediated by the G protein-coupled receptor CXCR6 because it was blocked by the G i protein inhibitor pertussis toxin. In contrast, the soluble CXCL16 chemokine enhanced proliferation, and this was also mediated by CXCR6 but not via G i protein. It is remarkable that both CXCR6 and CXCL16 are expressed by all mammary carcinomas because cells that lose either acquire a growth advantage and should be selected during tumor progression. This suggests an unknown important role in tumor formation. Proteases, possibly macrophage derived, might convert inhibitory transmembrane CXCL16 into the stimulatory chemokine.

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Section: Discussionmentioning

confidence: 99%

The Chemokine Receptor CXCR6 and Its Ligand CXCL16 Are Expressed in Carcinomas and Inhibit Proliferation

Meijer¹,

Ogink²,

Kreike

et al. 2008

Cancer Research

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“…A recent study showed that SOCS-1 increased and sustained the activation of p38 HOG in response to TNFa in murine ®broblasts, a response that was impaired in SOCS-1 de®cient cells (Morita et al, 2000). Although the pathway by which SOCS-1 couples to p38 HOG is unknown, activation of p38 HOG may be one mechanism of how SOCS-1 arrests cells transiting the cell cycle (Alderton et al, 2001;Bulavin et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

The tumor suppressor activity of SOCS-1

et al. 2002

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SOCS-1 is an inducible SH2-containing inhibitor of Jak kinases and as such can potently suppress cytokine signaling. SOCS-1 de®cient mice die within the ®rst three weeks of life from a myeloproliferative disorder driven by excessive interferon signaling. We report here that SOCS-1 inhibits proliferation signals induced by a variety of oncogenes active within the hematopoietic system. Ectopic expression of SOCS-1 abolished proliferation mediated by a constitutively active form of the KIT receptor, TEL-JAK2, and v-ABL, and reduced metastasis from BCR-ABL transformed cells. SOCS-1, however, did not interfere with v-SRC or RASV12 mediated cellular transformation. A mutant form of SOCS-1 unable to bind through its SH2 domain to tyrosine phosphorylated proteins could still inhibit KIT, but not TEL-JAK2, indicating multiple mechanisms for SOCS-1-mediated tumor suppression. We show that the steady state levels of TEL-JAK2 and to a greater extent v-ABL are diminished in the presence of SOCS-1. Lastly, we show that SOCS-1 7/7 ®broblasts are more sensitive than wild type ®broblasts to either spontaneous or oncogene-induced transformation. These data suggest that loss-of-function of SOCS-1 may collaborate with a variety of hematopoietic oncogenes to facilitate tumor progression.

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“…Results showed that in response to SB203580 treatment, expression of USP22 and the key regulator of cell cycle, p21, exhibited the inverse trend. A previous study has demonstrated that p38 MAPK participates in p21 upregulation, subsequently inhibiting cell growth (21). It is not fully understood how activated p38 MAPK can upregulate p21 expression.…”

Section: A C Bmentioning

confidence: 99%

p38 mitogen-activated protein kinase inhibits USP22 transcription in HeLa cells

et al. 2015

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Abstract. Elevated expression of ubiquitin-specific processing enzyme 22 (USP22) was identified in multiple types of human cancers, and was correlated with tumorigenesis and progression. Despite an increase in the numbers of studies in the physiological function of USP22, little is known regarding the regulation of its expression. The 5' flanking sequence of the USP22 gene was recently characterized. In the present study, USP22 transcription was regulated by p38 mitogen-activated protein kinase (MAPK). Treatment of human cervical carcinoma (HeLa) cells with SB203580, an inhibitor of p38 MAPK, enhanced basal USP22 promoter activity and mRNA abundance. Transfection of MAPK kinase 6 (MKK6), an upstream activator of p38 MAPK, resulted in a 40% decrease in USP22 mRNA, while the dominant negative MKK6 increased the transcription level of the USP22, similar to SB203580. Dual luciferase report assays showed that mutations of the Sp1 binding site ahead of the transcription start site abolished the promoting effect of the USP22 promoter by SB203580. Cisplatin, the activator of p38 MAPK, also suppressed USP22 expression. This suppression was blocked by SB203580. In conclusion, p38 MAPK acts as an upstream negative regulator of USP22 transcription in HeLa cells. IntroductionUbiquitin-specific processing enzyme 22 (USP22) is a novel deubiquitinating enzyme that can cleave ubiquitin (Ub) from Ub-conjugated protein substrates (1). As the subunit of the human SAGA coactivator complex, USP22 is linked to the regulation of gene transcription by deubiquitinating histones H2A and H2B (2,3). In addition, USP22 deubiquitinates intracellular protein, including the shelterin protein telomeric repeat binding factor 1 (4), the histone deacetylase sirtuin 1 (5) and the far upstream element-binding protein 1 fructose-1,6-bisphosphatase 1 (4), and therefore performs an extensive physiological function. A murine study showed that USP22 also regulates embryonic stem cell differentiation (6). In humans, the USP22 gene is located on chromosome 17, consists of 14 exons, and is transcribed and produced broadly across various tissues (7). Of note, elevated levels of USP22 have been identified in numerous types of human cancer, including colorectal (8) lung (9) and breast cancer (10). USP22 has been indicated in tumorigenesis. Deletion of USP22 leads to the accumulation of cells in the G 1 phase of the cell cycle (2). For these reasons, USP22 is a putative cancer stem cell marker. Reducing the rate of USP22 expression may be a suitable target for cancer therapy (11). However, the mechanisms that lead to USP22 transcriptional activation, particularly in the human tumor cells, remain unknown.Previously, USP22 transcription was activated by mitogen stimulation or viral infection in normal T and B lymphocytes (12), suggesting the regulation of USP22 gene expression occurs mainly at the transcriptional level. However, the mechanism in which signal transduction pathways regulate USP22 transcription is unclear. It is well-known that activation of the mito...

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High-Intensity p38 Kinase Activity Is Critical for p21^cip1 Induction and the Antiproliferative Function of G_i Protein-Coupled Receptors

Cited by 48 publications

References 40 publications

The Chemokine Receptor CXCR6 and Its Ligand CXCL16 Are Expressed in Carcinomas and Inhibit Proliferation

The Chemokine Receptor CXCR6 and Its Ligand CXCL16 Are Expressed in Carcinomas and Inhibit Proliferation

The tumor suppressor activity of SOCS-1

p38 mitogen-activated protein kinase inhibits USP22 transcription in HeLa cells

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