p38 MAPK Activation Selectively Induces Cell Death in K-ras-mutated Human Colon Cancer Cells through Regulation of Vitamin D Receptor

Qi, Xiaomei; Tang, Jun; Pramanik, Rocky; Schultz, Richard M.; Shirasawa, Senji; Sasazuki, Takehiko; Han, Jiahuai; Chen, Guan

doi:10.1074/jbc.m313964200

Cited by 60 publications

(55 citation statements)

References 67 publications

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“…The target sequence (5Ј-AAGGAGATCATGAAGGTGACG-3Ј) was cloned into the pSR vector, which was transfected into the packaging cells to produce the virus-containing supernatants for infection, as we previously described (32). Among four sequences analyzed, this siRNA yielded the most substantial effect on p38␥ depletion in several cell types and was consequently used for all analyses.…”

Section: Methodsmentioning

confidence: 99%

“…FLAG-tagged p38 isoform cDNAs in pcDNA3 vector and their dominant negative AGF counterparts were previously described (17,18). The adenovirus vector containing HA-tagged constitutively active MKK6 was used as previously described (17,32). HA-tagged K-Ras and H-Ras cDNAs (both with G12V mutation) were provided by Guthrie cDNA Resource Center and subcloned into retroviral vector LZRS (33).…”

Section: Methodsmentioning

confidence: 99%

“…ERK/MAPK activation has been shown to be both necessary and sufficient in transforming experimental NIH 3T3 cells (28,29), whereas the JNK pathway is also required for Ras transformation (30,31). On the contrary, activation of p38 MAPK is antagonistic to Ras activity, including inhibition of Ras-induced proliferation in NIH 3T3 cells (6), suppression of Ras transformation in RIE cells (30), and induction of K-Ras-dependent cell death in human colon cancer cells (32). In this study, we sought to test the hypothesis that endogenous p38 family members may regulate Ras activity by an isoform-specific mechanism.…”

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confidence: 99%

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Essential Role of p38γ in K-Ras Transformation Independent of Phosphorylation

Tang¹,

Qi²,

Mercola

et al. 2005

Journal of Biological Chemistry

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111

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Here we report that K-Ras activated p38␥, a p38 MAPK family member, by inducing its expression without increasing its phosphorylation and that depletion of induced p38␥ suppressed Ras transformation in rat intestinal epithelial cells. This p38␥ activity contrasts with that of its family member, p38␣, which is activated by Ras through phosphorylation, leading to an inhibition of Ras transformation. Mechanistic analyses showed that unphosphorylated p38␥ may promote Ras transformation through an increased complex formation with ERK proteins. Significantly, functional p38␥ protein was expressed only in K-ras-mutated human colon cancer cells, and p38␥ transcripts were ubiquitously increased in a set of primary human colon cancer tissues. These studies thus demonstrate the essential role of p38␥ in K-Ras transformation independent of phosphorylation, and elevated p38␥ may serve as a novel diagnostic marker and therapeutic target for human colon cancer.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Essential Role of p38γ in K-Ras Transformation Independent of Phosphorylation

Tang¹,

Qi²,

Mercola

et al. 2005

Journal of Biological Chemistry

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111

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“…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.…”

Section: Introductionmentioning

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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“…In response to Ras signaling, p38␣ phosphorylation is increased, and phosphorylated p38␣ then functions as a tumor suppressor in vitro (12,13) and in vivo (14,15), whereas p38␥ expression is increased, and resulting p38␥ in turn promotes the oncogenic process independently of (16 -18) and dependent on phosphorylation (19,20). In stress response, although p38␥ is similarly activated as pro-apoptotic p38␣, it plays an anti-apoptotic role under certain conditions (17,(21)(22)(23)(24).…”

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confidence: 99%

p38γ Mitogen-activated Protein Kinase Signals through Phosphorylating Its Phosphatase PTPH1 in Regulating Ras Protein Oncogenesis and Stress Response

Hou

Suresh

et al. 2012

Journal of Biological Chemistry

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Background:A cross-talk between a kinase and phosphatase plays a critical role in determining cellular fate. Results: We report that p38␥ phosphorylates its phosphatase PTPH1 in regulation of Ras oncogenesis and stress response. Conclusion:These results indicate that a MAPK can signal through its phosphatase. Significance: These studies reveal a novel mechanism by which a MAPK signals through its phosphatase to determine cellular outcomes.

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p38 MAPK Activation Selectively Induces Cell Death in K-ras-mutated Human Colon Cancer Cells through Regulation of Vitamin D Receptor

Cited by 60 publications

References 67 publications

Essential Role of p38γ in K-Ras Transformation Independent of Phosphorylation

Essential Role of p38γ in K-Ras Transformation Independent of Phosphorylation

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

p38γ Mitogen-activated Protein Kinase Signals through Phosphorylating Its Phosphatase PTPH1 in Regulating Ras Protein Oncogenesis and Stress Response

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