Defective TNF-α-Induced Apoptosis in STAT1-Null Cells Due to Low Constitutive Levels of Caspases

Kumar, Aseem; Commane, Mairead; Flickinger, Thomas W.; Horvath, Curt M.; Stark, George Stark

doi:10.1126/science.278.5343.1630

Cited by 457 publications

(372 citation statements)

References 20 publications

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“…Potential proapoptotic and significant prosurvival effects of STAT1 have been described previously (Shen et al, 2001;Stephanou and Latchman, 2003;Terui et al, 2004). Both effects were attributed to the ability of STAT1 to activate expression of either proapoptotic (Kumar et al, 1997;Stephanou et al, 2000Stephanou et al, , 2001 or prosurvival proteins (Stephanou et al, 1999;Madamanchi et al, 2001;Terui et al, 2004). We found here that in WT cells serine-phosphorylated STAT1 promotes cell survival through the regulation of expression of two known prosurvival genes, MCL-1 and HSP27 (Kabakov et al, 2003;Michels et al, 2005).…”

Section: Stat1 Is a Prosurvival Factor In Wilms' Tumorsupporting

confidence: 80%

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

et al. 2006

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Wilms' tumor (WT), one of the most common pediatric solid cancers, arises in the developing kidney as a result of genetic and epigenetic changes that lead to the abnormal proliferation and differentiation of the metanephric blastema. As activation of signal transducers and activators of transcription (STATs) plays an important role in the maintenance/growth and differentiation of the metanephric blastema, and constitutively activated STATs facilitate neoplastic behaviors of a variety of cancers, we hypothesized that dysregulation of STAT signaling may also contribute to WT pathogenesis. Accordingly, we evaluated STAT phosphorylation patterns in tumors and found that STAT1 was constitutively phosphorylated on serine 727 (S727) in 19 of 21 primary WT samples and two WT cell lines. An inactivating mutation of S727 to alanine reduced colony formation of WT cells in soft agar by more than 80% and induced apoptosis under conditions of growth stress. S727-phosphorylated STAT1 provided apoptotic resistance for WT cells via upregulation of expression of the heat-shock protein (HSP)27 and antiapoptotic protein myeloid cell leukemia (MCL)-1. The kinase responsible for STAT1 S727 phosphorylation in WT cells was identified based upon the use of selective inhibitors as protein kinase CK2, not p38, MAP-kinase kinase (MEK)1/2, phosphatidylinositol 3 0 -kinase, protein kinase C or Ca/calmodulindependent protein kinase II (CaMKII). The inhibition of CK2 blocked the anchorage-independent growth of WT cells and induced apoptosis under conditions of growth stress. Our findings suggest that serine-phosphorylated STAT1, as a downstream target of protein kinase CK2, plays a critical role in the pathogenesis of WT and possibly other neoplasms with similar STAT1 phosphorylation patterns.

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Section: Stat1 Is a Prosurvival Factor In Wilms' Tumorsupporting

confidence: 80%

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

et al. 2006

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“…These results also suggest a direct role for Unphosphorylated STAT6 increases COX-2 in NSCLC X Cui et al unphosphorylated STAT6 in tumorigenesis. Previous investigations have linked constitutive phosphorylated STATs to cancer progression, however, our study, together with other recent reports indicate that attention should now be expanded to encompass unphosphorylated STATs (Kumar et al, 1997;Chatterjee-Kishore et al, 2000;Yang et al, 2005). In summary, our study in human NSCLC cells demonstrates that unphosphorylated STAT6 contributes to constitutive COX-2 transcription via binding to the COX-2 promoter in association with transcription coactivator p300.…”

Section: Discussionmentioning

confidence: 60%

Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer

et al. 2007

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Cyclooxygenase-2 (COX-2) is frequently overexpressed in human cancers and contributes to the malignant phenotype. Our data indicate unphosphorylated signal transducers and activators of transcription 6 (STAT6) may transcriptionally upregulate COX-2 expression and protect against apoptosis in NSCLC cells. In A427 and H2122, NSCLC cell lines that constitutively express COX-2, only unphosphorylated STAT6 was detectable by western blot, thus, all of the following STAT6-dependent effects are attributed to the unphosphorylated protein.In both cell lines, small-interfering RNA-mediated knockdown of STAT6 or stable expression of dominant-negative STAT6 decreased COX-2 expression. In contrast, transfection with a phosphorylation-deficient mutant STAT6 increased COX-2 levels. Immunofluorescent staining revealed the presence of STAT6 in H2122 nuclei, suggesting a direct role in gene regulation for the unphosphorylated protein. Consistent with this hypothesis, unphosphorylated STAT6 increased luciferase expression from a COX-2 promoter reporter construct. STAT6 coimmunoprecipitated with the transcriptional co-activator, p300, and chromatin immunoprecipitation assays demonstrated that these proteins bind a consensus STAT6 binding site located within the COX-2 promoter. STAT6 DNA-binding specificity was confirmed by electrophoretic mobility shift assay. As COX-2 over-expression has been clearly linked to apoptosis resistance and other hallmarks of malignancy, these findings suggest a novel role of unphosphorylated STAT6 in the pathogenesis of nonsmall cell lung cancer.

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“…In accord with these results, the transcriptional activity mediated by ISGF3 or Stat1 can be enhanced by constitutively active MKK6, the upstream activator of p38. In PKR null cells, signal transduction and gene induction by IFN-g is attenuated as a result of de®cient activation of the transcription factor IRF-1 (Kumar et al, 1997). However, in PKR null cells, there is a defect in IFN-g-induced phosphorylation of Ser727 on Stat1 (Ramana et al submitted) suggesting that PKR might act upstream of p38.…”

Section: Pkr and P38 Mapkmentioning

confidence: 99%

PKR; a sentinel kinase for cellular stress

1999

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Defective TNF-α-Induced Apoptosis in STAT1-Null Cells Due to Low Constitutive Levels of Caspases

Cited by 457 publications

References 20 publications

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer

PKR; a sentinel kinase for cellular stress

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