Genetic inactivation of <i>Par4</i> results in hyperactivation of NF‐κB and impairment of JNK and p38

Garcı́a-Cao, Isabel; Lafuente, María José; Criado, Luis M.; Diaz-Meco, Marı́a T.; Serrano, Manuel; Moscat, Jorge

doi:10.1038/sj.embor.embor769

Cited by 58 publications

(88 citation statements)

References 18 publications

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“…This was the case, as cisplatin-activated p38 MAP kinase to a greater extent in cells depleted of PKCi. This result is consistent with previous observations on the effect of atypical PKC inhibition by Par-4, an endogenous inhibitor of PKCz and PKCi (Berra et al, 1997;Garcia-Cao et al, 2003); inhibition of PKCi by this method also enhanced p38 MAP kinase signaling. Overexpression of GMFb in U87MG cells reproduced the effects of PKCi depletion on both p38 MAP kinase activation and cisplatin cytotoxicity.…”

Section: Discussionsupporting

confidence: 82%

Protection of glioblastoma cells from cisplatin cytotoxicity via protein kinase Cι-mediated attenuation of p38 MAP kinase signaling

et al. 2005

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Glioblastoma multiforme is an aggressive form of brain cancer that responds poorly to chemotherapy and is generally incurable. The basis for the poor response of this cancer to chemotherapy is not well understood. The atypical protein kinases C (PKCi and PKCf) have previously been implicated in leukaemia cell chemoresistance. To assess the role of atypical PKC in glioblastoma cell chemoresistance, RNA interference was used to deplete human glioblastoma cells of PKCi. Transfection of cells with either of two different RNA duplexes specific for PKCi caused a partial sensitisation to cell death induced by the chemotherapy agent cisplatin. To screen for possible mechanisms for PKCi-mediated chemoresistance, microarray analysis of gene expression was performed on RNA from glioblastoma cells that were either untreated or depleted of PKCi. This identified sets of genes that were regulated either positively or negatively by PKCi. Within the set of genes that were negatively regulated by PKCi, the function of the gene coding for GMFb, an enhancer of p38 mitogen-activated protein kinase (MAP kinase) signaling, was investigated further, as the p38 MAP kinase pathway has been previously identified as a key mediator of cisplatin cytotoxicity. The expression of both GMFb mRNA and protein increased upon PKCi depletion, and this was accompanied by an increase in cisplatin-activated p38 MAP kinase signaling. Transient overexpression of GMFb increased cisplatinactivated p38 MAP kinase signaling and also sensitised cells to cisplatin cytotoxicity. The increase in cisplatin cytotoxicity seen with PKCi depletion was blocked by the p38 MAP kinase inhibitor SKF86002. These data show that PKCi can confer partial resistance to cisplatin in glioblastoma cells by suppressing GMFb-mediated enhancement of p38 MAP kinase signaling.

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Section: Discussionsupporting

confidence: 82%

Protection of glioblastoma cells from cisplatin cytotoxicity via protein kinase Cι-mediated attenuation of p38 MAP kinase signaling

et al. 2005

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“…Part of this effect has been proposed to result from activation of the Fas/FasL-mediated apoptosis pathway (Chakraborty et al 2001). More recently, functional and genetic analyses indicated that par-4 functions as a negative regulator of the protein kinase C-nuclear factor-B (NF-B)-X-linked inhibitor of apoptosis protein (XIAP) pathway (Garcia-Cao et al 2003. In addition, par-4 has also been identified as a transcription cofactor for the Wilms' tumor suppressor gene (WT1) through direct interaction with the zinc-finger DBD of WT1 (Johnstone et al 1996, Richard et al 2001.…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor and prostate apoptosis response factor-4 target the c-FLIP gene to determine survival and apoptosis in the prostate gland

Gao¹,

Wang²,

Lee³

et al. 2006

Journal of Molecular Endocrinology

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Androgen receptor (AR) is a ligand-activated transcription factor that mediates the action of androgens and is essential for the growth, function, and cell differentiation of the prostate gland. Here, we demonstrated that the prostate apoptosis response factor-4 (par-4) functions as a novel AR coactivator. Par-4 physically interacted with the DNA-binding domain of AR, enhanced AR interaction with DNA, and increased AR-dependent transcription. Par-4 enhanced the c-FLIP promoter activity and was recruited on to the c-FLIP gene in the presence of androgens, and the dominant-negative par-4 decreased c-FLIP expression. These results suggest that, in addition to its proapoptotic function, par-4 acts as a novel transcription cofactor for AR to target c-FLIP gene expression. In addition, we demonstrated that loss of c-FLIP expression was essential for castration-induced apoptosis in the prostate gland and that enhanced c-FLIP expression was associated with prostate cancer progression to the androgen-resistant stage. Our data shed light on a transcription-mediated mechanism for the effects of the AR pathway on cell survival and apoptosis.

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“…27 TRAF5, another component of the same cluster (P9), also plays a role as an adapter protein in 29 Negative regulators of the NF-kB pathway, such as PAWR (PAR4), have been shown to interact with and inhibit atypical protein kinase C isoforms, functioning as a negative regulator of the NF-kB pathway. 30 Additionally, Fas-associated factor-1, FAF1, inhibits NF-kB activity by interfering with nuclear translocation of the RelA (p65) subunit of NF-kB. 31 This group of patients is also recognized by the expression of the genes defined in the P14 cluster: LPL, WSB2.…”

Section: Discussionmentioning

confidence: 99%

Molecular heterogeneity in chronic lymphocytic leukemia is dependent on BCR signaling: clinical correlation

et al. 2007

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Chronic lymphocytic leukemia (CLL), the most frequent form of adult leukemia in Western countries, is characterized by a highly variable clinical course. Expression profiling of a series of 160 CLL patients allowed interrogating the genes presumably playing a role in pathogenesis, relating the expression of functionally relevant signatures with the time to treatment. First, we identified genes relevant to the biology and prognosis of CLL to build a CLL disease-specific oligonucleotide microarray. Second, we hybridized a training series on the CLLspecific chip, generating a biology-based predictive model. Finally, this model was validated in a new CLL series. Clinical variability in CLL is related with the expression of two gene clusters, associated with B-cell receptor (BCR) signaling and mitogen-activated protein kinase (MAPK) activation, including nuclear factor-jB1 (NF-jB1). The expression of these clusters identifies three risk-score groups with treatment-free survival probabilities at 5 years of 83, 50 and 17%. This molecular predictor can be applied to early clinical stages of CLL. This signature is related to immunoglobulin variable region somatic hypermutation and surrogate markers. There is a molecular heterogeneity in CLL, dependent on the expression of genes defining BCR and MAPK/NF-jB clusters, which can be used to predict time to treatment in early clinical stages.

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Genetic inactivation of Par4 results in hyperactivation of NF‐κB and impairment of JNK and p38

Cited by 58 publications

References 18 publications

Protection of glioblastoma cells from cisplatin cytotoxicity via protein kinase Cι-mediated attenuation of p38 MAP kinase signaling

Protection of glioblastoma cells from cisplatin cytotoxicity via protein kinase Cι-mediated attenuation of p38 MAP kinase signaling

Androgen receptor and prostate apoptosis response factor-4 target the c-FLIP gene to determine survival and apoptosis in the prostate gland

Molecular heterogeneity in chronic lymphocytic leukemia is dependent on BCR signaling: clinical correlation

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