STAT-1 facilitates the ATM activated checkpoint pathway following DNA damage

Townsend, Paul A.; Cragg, Mark S.; Davidson, Sean M.; McCormick, James A.; Barry, Seán P.; Lawrence, Kevin M.; Knight, Richard; Hubank, Michael; Chen, Phang-Lang; Latchman, David S.; Stephanou, Anastasis

doi:10.1242/jcs.01728

Cited by 58 publications

(60 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Townsend and colleagues have also reported enhanced Stat1 expression in p53-KO (22). It is well known that radiation-induced ATM activation leads to the accumulation of p53.…”

Section: Discussionmentioning

confidence: 89%

Activation of Interferon-Stimulated Genes by γ-Ray Irradiation Independently of the Ataxia Telangiectasia Mutated–p53 Pathway

Sugihara

Murano

Nakamura

et al. 2011

Molecular Cancer Research

View full text Add to dashboard Cite

The ataxia telangiectasia mutated (ATM)-p53 pathway is a well-known main signal transduction pathway for cellular responses, which is activated by g-ray irradiation. Microarray analysis showed changes in the expressions of IFN-stimulated genes (ISG) in g-ray-irradiated Balb/cA/Atm-deficient mouse embryonic fibroblasts (MEF) (ATM-KO), indicating that another pathway for cellular responses besides the ATM-p53 pathway was activated by g-ray irradiation. The basal expression levels of Irf7 and Stat1 in ATM-KO and p53-deficient MEFs (p53-KO) were higher than those in Atm-wild-type MEFs (ATM-WT) and p53-wild-type MEFs (p53-WT), respectively. Irradiation stimulated the expressions of Irf7 and Stat1 in ATM-KO, p53-KO, ATM-WT, and p53-WT, indicating that upregulation of Irf7 and Stat1 expressions by irradiation did not depend on the ATM-p53 pathway. When conditioned medium (CM) obtained from irradiated ATM-WT or ATM-KO was added to nonirradiated MEFs, the expressions of Irf7 and Stat1 increased. We predicted that gene activation in nonirradiated MEFs was caused by IFN-a/b. Unexpectedly, significant amount of IFN-a/b could not be detected in the CM from irradiated ATM-WT or ATM-KO. Meanwhile, increased expression of Ccl5 (RANTES) protein was detected in the CM from irradiated MEFs. These results indicate that ISGs were activated by g-ray irradiation independently of the ATM-p53 pathway and gene activation was caused by radiation-induced soluble factors. Mol Cancer Res; 9(4); 476-84. Ó2011 AACR.

show abstract

“…Townsend and colleagues have also reported enhanced Stat1 expression in p53-KO (22). It is well known that radiation-induced ATM activation leads to the accumulation of p53.…”

Section: Discussionmentioning

confidence: 89%

Activation of Interferon-Stimulated Genes by γ-Ray Irradiation Independently of the Ataxia Telangiectasia Mutated–p53 Pathway

Sugihara

Murano

Nakamura

et al. 2011

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…In case DNA repair is not possible, these checkpoints initiate apoptosis to remove damaged cells. 39 Another report demonstrated that STAT1 is required for the transcriptional up-regulation of 2 important mediators of ATM checkpoint activation, 53BP1 and MDC1, 42 suggesting the hypothesis that STAT1 can enhance the action of DNAdamaging drugs by its influence on the ATM checkpoint pathway.…”

Section: Discussionmentioning

confidence: 99%

“…2). This could be the result of a defective ATM checkpoint pathway, requiring STAT1 signaling, 42 leading to an increased accumulation of drug-induced mutations. It remains to be seen whether these patients experience a tumor.…”

Section: Discussionmentioning

confidence: 99%

STAT1 activation in squamous cell cancer of the oral cavity

Laimer¹,

Spizzo²,

Obrist³

et al. 2007

Cancer

View full text Add to dashboard Cite

Thermal degradation of poly(dimethylsilylene) homopolymer (PDMS) and poly(tetramethyldisilylene‐co‐styrene) copolymer (PTMDSS) was investigated by pyrolysis‐gas chromatography and thermogravimetry (TG). PDMS decomposes by depolymerization, producing linear and cyclic oligomeric products, whereas PTMDSS decomposes by random degradation along the chain resulting in each monomeric product and various other combination products. The homopolymer was found to be much less stable than the copolymer. The decomposition mechanisms leading to the formation of various products are shown. The kinetic parameters of thermal degradation were evaluated by different integral methods using TG data. The activation energies of decomposition (E) for the homopolymer and the copolymer are found to be 122 and 181 kJ/mol, respectively, and the corresponding values of order of reaction are 1 and 1.5. The observed difference in the thermal stability and the values of the kinetic parameters for decomposition of these polymers are explained in relation with the mechanism of decomposition. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci, 2006

show abstract

“…Although Bcl-xl and XIAP are bona fide antiapoptotic proteins, p27 Kip1 may also contribute to survival by inhibiting cell cycle progression and blocking the effects of chemotherapeutic drugs that are effective in proliferating cells (66). Some studies, however, indicated that Stat1 can act as a checkpoint in DNA-damaging chemotherapies and synergize with either p53 or IFNs to induce cell death in response to doxorubicin treatment (67)(68)(69). Stat1 function in cell survival as well as cell death may be explained by its ability to respond to drugs via pathways that are controlled by its phosphorylation in a temporal fashion.…”

Section: Stat1 Protects Cells From the Antiproliferative Effects Of Amentioning

confidence: 99%

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

Wang

Patsis

Koromilas

2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The signal transducer and activator of transcription 1 (Stat1) functions as a tumor suppressor via immune regulatory and cell-autonomous pathways. Herein, we report a previously unidentified cell-autonomous Stat1 function, which is its ability to exhibit both antiproliferative and prosurvival properties by facilitating translation of mRNAs encoding for the cyclin-dependent kinase inhibitor p27Kip1 and antiapoptotic proteins X-linked inhibitor of apoptosis and B-cell lymphoma xl. Translation of the select mRNAs requires the transcriptional function of Stat1, resulting in the up-regulation of the p110γ subunit of phosphoinositide 3-kinase (PI3K) class IB and increased expression of the translational repressor translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). Increased PI3Kγ signaling promotes the degradation of the eIF4A inhibitor programmed cell death protein 4, which favors the cap-independent translation of the select mRNAs under conditions of general inhibition of protein synthesis by up-regulated eIF4E-binding protein 1. As such, Stat1 inhibits cell proliferation but also renders cells increasingly resistant to antiproliferative effects of pharmacological inhibitors of PI3K and/or mammalian target of rapamycin. Stat1 also protects Ras-transformed cells from the genotoxic effects of doxorubicin in culture and immune-deficient mice. Our findings demonstrate an important role of mRNA translation in the cell-autonomous Stat1 functions, with implications in tumor growth and treatment with chemotherapeutic drugs.

show abstract

STAT-1 facilitates the ATM activated checkpoint pathway following DNA damage

Cited by 58 publications

References 50 publications

Activation of Interferon-Stimulated Genes by γ-Ray Irradiation Independently of the Ataxia Telangiectasia Mutated–p53 Pathway

Activation of Interferon-Stimulated Genes by γ-Ray Irradiation Independently of the Ataxia Telangiectasia Mutated–p53 Pathway

STAT1 activation in squamous cell cancer of the oral cavity

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

Contact Info

Product

Resources

About