JNK targets p53 ubiquitination and degradation in nonstressed cells

Fuchs, Serge Y.; Adler, Victor; Buschmann, Thomas; Yin, Zhimin; Wu, Xiangwei; Jones, Stephen N.; Ronai, Ze’ev

doi:10.1101/gad.12.17.2658

Cited by 305 publications

(285 citation statements)

References 33 publications

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“…Western blotting and JNK inhibition demonstrated that the constitutive JNK signal is required for SP1 expression. JNK pathway activation has been shown to play a role in the stability of transcription factors, which may also be the basis for the effect of JNK inhibition on SP1 expression seen in this study (55)(56)(57). Posttranslational modifications of SP1 have been implicated in the regulation of SP1 activity.…”

Section: Discussionmentioning

confidence: 54%

JNK MAPK Pathway Regulates Constitutive Transcription of CCL5 by Human NK Cells through SP1

Kumar

Hosse

Toerne

et al. 2009

The Journal of Immunology

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N atural killer cells have features similar to CD8 ϩ T cells in that they recognize and lyse virally infected and neoplastic cells; express receptors such as CD28, CD43, and 2B4; and contain cytolytic granules (1-6). The activation of NK surface receptors triggers microtubule organization, granule polarization, and cytotoxicity signals through both ERK2 and JNK1 phosphorylation pathways (7,8).The chemokine CCL5 has been suggested to act as an important mediator of diverse inflammatory processes (9 -11). In CTL, the protein is associated with the development and expression of effector function (12)(13)(14). In CD8 ϩ T cells, CCL5 transcription occurs late (3-5 days) after the activation of naive cells and is coincident with the up-regulation of perforin, the granzymes, and granulysin (15)(16)(17). A complex of nuclear proteins recruited to the promoter by Krü ppel-like factor 13 (KLF13) 3 controls the transcription of CCL5 in CTL (18,19). KLF13 is translationally regulated and appears several days after T cell activation. The p38 and ERK1/2 MAPK pathways control KLF13 gene expression, whereas pre-mRNA processing factor 4 homolog B, a member of the MAPK family, regulates KLF13 phosphorylation in T cells and by extension CCL5 expression (20,21). In NK cells, the MAPKs and PI3K pathways are also involved in triggering the polarized release of cytolytic granules (7,8,(22)(23)(24); however, the role of these pathways in the control of CCL5 expression in NK cells has not been investigated.We report in this study that unlike in T cells, CCL5 mRNA is constitutively transcribed and translated in peripheral blood NK cells. The CCL5 protein is localized to secretory vesicles that are distinct from the cytolytic granules. The constitutive transcription of CCL5 mRNA in NK cells is mediated through binding of the SP1 transcription factor to a site just upstream from the TATA box of the CCL5 gene. The JNK/MAPK pathway in turn controls SP1 expression and, through this, constitutive CCL5 transcription. Materials and Methods Abs, inhibitors, and oligonucleotidesPhospho-specific Abs that recognize the activated forms of phospho-stressactivated protein kinase/JNK (Thr 183 /Tyr 185 ) and inactive forms of stressactivated protein kinase/JNK were purchased from Cell Signaling Technology (catalog 9251 and 9252). The Abs for NF-B, p50, p52, p65, SP1, and SP3 were purchased from Upstate Biotechnology (catalog 06-886, 06-413, 06-418, 07-645, and 07-107, respectively), and ␤ actin for proteinloading control and KLF13 was purchased from Abcam (catalog ab8227 and ab1127). Primary Abs were as follows: mouse IgG2b-anti-human CCL5 VL1 or VL2 hybridoma supernatant (25), mouse IgG1 anti-human granzyme B (Serotec; catalog MCA2120PE), mouse anti-human perforin (BD Biosciences; catalog 556434), goat anti-mouse IgG1 CD3 Pacific Blue (DakoCytomation; PB982), goat anti-mouse IgG1 CD56 allophycocyanin conjugated (BD Biosciences; catalog IM2474), and rabbit anti-human CD8 (Neomarkers; catalog RM-9116-R7 The costs of publication of this article were defray...

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Section: Discussionmentioning

confidence: 54%

JNK MAPK Pathway Regulates Constitutive Transcription of CCL5 by Human NK Cells through SP1

Kumar

Hosse

Toerne

et al. 2009

The Journal of Immunology

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“…105 JNK has also been found to form associations with p53 in nonstressed cells and it has been proposed to mediate p53 ubiquitination and degradation by forming an adaptor-molecule in the E3 ubiquitin-ligase complex. 106 This JNK-mediated degradation is MDM2-independent.…”

Section: Inhibition Of Mdm2-mediated Degradation Of P53 By Other Mechmentioning

confidence: 99%

Regulation and activation of p53 and its family members

Lohrum¹,

Kh²

1999

Cell Death Differ

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Regulation of the p53 tumor suppressor protein occurs to a large extent through control of protein stability, and the MDM2 protein has been shown to play a key role in targeting p53 for degradation. Stress signals that activate the p53 response lead to stabilization of p53 through inhibition of MDM2 mediated degradation, and it is becoming evident that a number of mechanisms exist to abrogate this activity of MDM2. Other members of the p53 protein family may also be regulated through protein stability, although MDM2 is not responsible for the degradation of p73. Nevertheless, interactions of p63 and p73 with MDM2 or p53 have been described, suggesting that each of the p53-related proteins can play some role in regulating the activity of the others Keywords: p53; p73; p63; MDM2; E2F-1; protein stability Common themes, different players: Regulation of p53, p73 and p63The tumor suppressor protein p53 has been studied intensively over the past decade, and it is clear that p53 activity plays an important role in preventing tumor development. p53 is a potent inhibitor of cell growth and so control of p53 activity is essential during normal growth and development. Regulation of p53 has been described at the level of transcription and translation, 1 and through allosteric regulation of p53 conformation. 2 However, by far the most attention has been directed to modulation of p53 protein stability which appears to be one of the critical mechanism by which p53 function is regulated, and the mechanisms through which p53 is degraded have been under intense scrutiny over the past few years. The recent identification of the p53 related proteins, p63 and p73, has raised the question of whether all the family members are regulated through the same mechanisms to allow for a coordinated response, or whether each protein is subject to independent regulation. This review aims to summarize the present models on how the p53 protein is degraded and how these pathways are inhibited to allow activation of a p53 response, with comparisons to our, as yet, less comprehensive understanding of how p73 and p63 activity is controlled.

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“…As p53 ubiquitination was not completely abolished in extracts from MDM2-deficient cells, the existence of other molecules capable of targeting p53 for degradation was suggested. 125 Indeed, it was found that p53 can also be targeted for proteasomal degradation by three other E3-ubiquitin ligases namely Cop1, Pirh2 and synoviolin, from which the former two are regulated in a p53-dependent manner following IR. 36,37 Similar to the effects observed with increased MDM2 levels, overexpression of either Cop1 or Pirh2 resulted in the proteasomal destruction of p53 and concomitantly protected the cells from growth inhibition and apoptosis.…”

Section: P53-binding Proteinsmentioning

confidence: 99%

The dark side of a tumor suppressor: anti-apoptotic p53

2008

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Depending on multiple factors DNA damage leads either to cell cycle arrest or apoptosis. One of the main players deciding the fate of a cell is the tumor suppressor p53 that modulates these responses in a transcription-dependent and -independent manner. Over the past few years, however, strong evidence accumulated that p53 engages also powerful pro-survival pathways by transcriptionally activating a multitude of genes whose products efficiently counteract apoptosis. Our review summarizes the current knowledge concerning approximately forty p53-regulated proteins that exert their anti-apoptotic potential by interfering with diverse cellular processes. These activities are surely essential for normal development and maintenance of a healthy organism, but may easily turn into the dark side of the tumor suppressor p53 contributing to tumorigenesis.

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JNK targets p53 ubiquitination and degradation in nonstressed cells

Cited by 305 publications

References 33 publications

JNK MAPK Pathway Regulates Constitutive Transcription of CCL5 by Human NK Cells through SP1

JNK MAPK Pathway Regulates Constitutive Transcription of CCL5 by Human NK Cells through SP1

Regulation and activation of p53 and its family members

The dark side of a tumor suppressor: anti-apoptotic p53

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