Conditional expression of MAP kinase phosphatase-2 protects against genotoxic stress-induced apoptosis by binding and selective dephosphorylation of nuclear activated c-jun N-terminal kinase

Cadalbert, Laurence; Sloss, Callum M.; Cameron, Pamela; Plevin, Robin

doi:10.1016/j.cellsig.2005.01.003

Cited by 51 publications

(51 citation statements)

References 40 publications

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“…We found that the expression of MKP-2 is significantly induced in RET-MEN2A-driven carcinoma cells and plays an important role in their proliferation both in vitro and in vivo. MKP-2 is a dual-specificity phosphatase known to inactivate MAPKs (Farooq and Zhou, 2004;Cadalbert et al, 2005;Dickinson and Keyse, 2006;Owens and Keyse, 2007), as was confirmed by the present study (Figure 2). However, despite an important function of MKP-2 in regulating the activity of MAPKs, evidence is limited for its role in tumor progression.…”

Section: Discussionsupporting

confidence: 74%

“…MKP-2 exhibits phosphatase activity toward p42/44 and p38 MAPKs, but not JNK, in MKK-f cells Although previous studies have shown that MKP-2, when activated by p42/44 MAPK, possesses the activity to dephosphorylate p42/44 and p38 MAPKs, and JNK, its substrate specificity remains controversial (Farooq and Zhou, 2004;Cadalbert et al, 2005;Dickinson and Keyse, 2006;Owens and Keyse, 2007). To confirm the phosphatase activity of MKP-2, HEK293 cells were transfected with mouse wild-type MKP-2 and its catalytically inactive mutant (MKP-2 C280S), in which the cysteine at residue 280 in the catalytic domain was mutated to serine (Cadalbert et al, 2005).…”

Section: Resultsmentioning

confidence: 98%

“…To confirm the phosphatase activity of MKP-2, HEK293 cells were transfected with mouse wild-type MKP-2 and its catalytically inactive mutant (MKP-2 C280S), in which the cysteine at residue 280 in the catalytic domain was mutated to serine (Cadalbert et al, 2005). Epidermal growth factor (EGF)-mediated phosphorylation of p42/ 44 MAPK was attenuated by exogenous expression of wild-type MKP-2 and enhanced by the C280S mutant ( Figure 2a).…”

Section: Resultsmentioning

confidence: 99%

“…Human fulllength MKP-2 cDNA was isolated by PCR from a cDNA library prepared using RNA of TGW neuroblastoma cells. A catalytically inactive mutant of MKP-2 (C280S) (Cadalbert et al, 2005) was generated using the QuikChange Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA, USA) according to the manufacturer's protocol. The cDNAs were subcloned into the pEF1-myc vector (Invitrogen) and used for experiments.…”

Section: Plasmid Constructionmentioning

confidence: 99%

“…MKP-2 was first identified as a dual-specificity phosphatase that selectively dephosphorylates the p42/44 MAPK, p38 MAPK and JNK (Guan and Butch, 1995;Misra-Press et al, 1995;Farooq and Zhou, 2004;Cadalbert et al, 2005;Dickinson and Keyse, 2006;Owens and Keyse, 2007). Interestingly, despite the activity of MKP-2 in inhibiting the activity of the MAPKs, depletion of MKP-2 by RNA interference resulted in deregulation of the cell cycle and proliferative inhibition of MKK-f, a cell line that was established from a mammary carcinoma developed in a RET-MEN2A transgenic mouse (Kawai et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice

et al. 2008

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Germline mutations in the RET tyrosine kinase gene are responsible for the development of multiple endocrine neoplasia 2A and 2B (MEN2A and MEN2B). However, knowledge of the fundamental principles that determine the mutant RET-mediated signaling remains elusive. Here, we report increased expression of mitogen-activated protein kinase phosphatase-2 (MKP-2) in carcinomas developed in transgenic mice carrying RET with the MEN2A mutation (RET-MEN2A). The expression of MKP-2 was not only induced by RET-MEN2A or RET-MEN2B mutant proteins but also by the activation of endogenous RET by its ligand, glial cell line-derived neurotrophic factor (GDNF). MKP-2 expression was also evident in the MKK-f cell line, which was established from a mammary tumor developed in a RET-MEN2A transgenic mouse. Inhibition of MKP-2 attenuated the in vitro and in vivo proliferation of MKK-f cells, which was mediated by the suppression of cyclin B1 expression. Furthermore, we found that MKP-2 is highly expressed in medullary thyroid carcinomas derived from MEN2A patients. These findings suggest that the increased expression of MKP-2 may play a crucial role in oncogenic signaling downstream of mutant RET, leading to deregulation of cell cycle.

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Section: Discussionsupporting

confidence: 74%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Plasmid Constructionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice

et al. 2008

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Expression of the MAP kinase phosphatase DUSP4 is associated with microsatellite instability in colorectal cancer (CRC) and causes increased cell proliferation

Gröschl

Bettstetter

Giedl

et al. 2012

Intl Journal of Cancer

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DUSP4 (MKP-2), a member of the mitogen-activated protein kinase phosphatase (MKP) family and potential tumor suppressor, negatively regulates the MAPKs (mitogen-activated protein kinases) ERK, p38 and JNK. MAPKs play a crucial role in cancer development and progression. Previously, using microarray analyses we found a conspicuously frequent overexpression of DUSP4 in colorectal cancer (CRC) with high frequent microsatellite instability (MSI-H) compared to microsatellite stable (MSS) CRC. Here we studied DUSP4 expression on mRNA level in 38 CRC (19 MSI-H and 19 MSS) compared to matched normal tissue as well as in CRC cell lines by RT-qPCR. DUSP4 was overexpressed in all 19 MSI-H tumors and in 14 MSS tumors. Median expression levels in MSI-H tumors were significantly higher than in MSS-tumors (p < 0.001). Consistently, MSI-H CRC cell lines showed 6.8-fold higher DUSP4 mRNA levels than MSS cell lines. DUSP4 expression was not regulated by promoter methylation since no methylation was found by quantitative methylation analysis of DUSP4 promoter in CRC cell lines neither in tumor samples. Furthermore, no DUSP4 mutation was found on genomic DNA level in four CRC cell lines. DUSP4 overexpression in CRC cell lines through DUSP4 transfection caused upregulated expression of MAPK targets CDC25A, CCND1, EGR1, FOS, MYC and CDKN1A in HCT116 as well as downregulation of mismatch repair gene MSH2 in SW480. Furthermore, DUSP4 overexpression led to increased proliferation in CRC cell lines. Our findings suggest that DUSP4 acts as an important regulator of cell growth within the MAPK pathway and causes enhanced cell growth in MSI-H CRC.Dual-specificity protein phosphatases (DUSPs) are members of the type I cysteine-based protein-tyrosine phosphatase superfamily. A subgroup of DUSPs is known as mitogen-activated protein kinase phosphatases (MKPs) which plays a crucial role in regulating the tumor relevant MAP kinase (mitogen-activated protein kinase) pathways which in turn drive proliferation, differentiation, 1-5 apoptosis and inflammation. 6All MKPs carry an N-terminal kinase interaction motive (KIM), essential for substrate binding, and a C-terminal catalytic domain for substrate dephosphorylation. 7 MKPs negatively regulate MAP kinase signals and thus provide a negative feedback mechanism for MAP kinase activity [8][9][10][11] by dephosphorylating the phospho-tyrosine and phospho-threonine residues within the T-X-Y activation site located in all MAP kinases. 12 DUSP4, also called MKP2, is a member of the inducible nuclear MKP group and specifically dephosphorylates the MAP kinases ERK1/2, p38 and JNK.13 DUSP4 expression has been confirmed in human melanoma cell lines 14 and ovarian cancer in serous borderline tumors but not in serous carcinoma. 15 In mouse models, DUSP4 has been associated with regulatory mechanisms in inflammatory response in sepsis. 16 Studies in breast cancer are controversial as DUSP4 expression is reported in primary tumor tissue 17 but can also be lost in early-onset and high-grade tumors indicating that...

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Crystal structure of the catalytic domain of human MKP‐2 reveals a 24‐mer assembly

Jeong¹,

Jung²,

Yoon³

et al. 2009

Proteins

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Conditional expression of MAP kinase phosphatase-2 protects against genotoxic stress-induced apoptosis by binding and selective dephosphorylation of nuclear activated c-jun N-terminal kinase

Cited by 51 publications

References 40 publications

Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice

Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice

Expression of the MAP kinase phosphatase DUSP4 is associated with microsatellite instability in colorectal cancer (CRC) and causes increased cell proliferation

Crystal structure of the catalytic domain of human MKP‐2 reveals a 24‐mer assembly

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