Interferon-γ Induced Medulloblastoma in the Developing Cerebellum

Lin, Wensheng; Kemper, April; McCarthy, Ken D.; Pytel, Peter; Wang, Jian Ping; Campbell, Iain L.; Utset, Manuel F.; Popko, Brian

doi:10.1523/jneurosci.2604-04.2004

Cited by 107 publications

(121 citation statements)

References 43 publications

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“…However, STAT1 expression is frequently upregulated in tumors (Frank et al, 1997;Spiekermann et al, 2001;Widschwendter et al, 2002;Benekli et al, 2003;Hudelist et al, 2005) and associated with prosurvival functions under conditions of growth stress, such as X-irradiation (Khodarev et al, 2004), or anticancer therapy (Friedberg et al, 2004;Roberts et al, 2005). Even ectopic expression of IFNg can support tumor development via STAT1 activation (Wang et al, 2000;Lin et al, 2004). Taken together, these data suggest that STAT1 activity is complex and probably context dependent and that STAT1 may indeed function in an oncogenic capacity.…”

Section: Stat1 Is a Prosurvival Factor In Wilms' Tumormentioning

confidence: 98%

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' Tumormentioning

confidence: 98%

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

et al. 2006

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“…7,8 We have generated transgenic mice that allow for the temporally controlled delivery of IFN-␥ to the CNS using the tetracycline-controllable system. 24 The expression of the IFN-␥ transgene is repressed in GFAP/tTA; TRE/IFN-␥ double-transgenic mice treated with doxycycline solution from conception (IFN-␥ CNSϪ mice). The levels of IFN-␥ become detectable at approximately postnatal day 10 (P10) in the CNS of GFAP/tTA; TRE/IFN-␥ double-transgenic mice that are released from doxycycline solution at embryonic day 14 (E14, IFN-␥ CNSϩ mice).…”

Section: Gadd34 Inactivation Increased the Levels Of P-eif2␣ In Oligomentioning

confidence: 99%

Enhanced Integrated Stress Response Promotes Myelinating Oligodendrocyte Survival in Response to Interferon-γ

Lin

Kunkler

Harding

et al. 2008

The American Journal of Pathology

141

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The T-cell-derived, pleiotropic cytokine interferon (IFN)-␥ is believed to play a key regulatory role in immune-mediated demyelinating disorders of the central nervous system, including multiple sclerosis and experimental autoimmune encephalomyelitis. Our previous work has demonstrated that the endoplasmic reticulum (ER) stress response modulates the response of oligodendrocytes to this cytokine. The ER stress response activates the pancreatic ER kinase, which coordinates an adaptive program known as the integrated stress response by phosphorylating translation initiation factor 2␣ (eIF2␣). In this study, we found that growth arrest and DNA damage 34 (GADD34), a stress-inducible regulatory subunit of a phosphatase complex that dephosphorylates eIF2␣, was selectively up-regulated in myelinating oligodendrocytes in mice that ectopically expressed IFN-␥ in the central nervous system. We also found that a GADD34 mutant strain of mice displayed increased levels of phosphorylated eIF2␣ (p-eIF2␣) in myelinating oligodendrocytes when exposure to IFN-␥, as well as diminished oligodendrocyte loss and hypomyelination. Furthermore, treatment with salubrinal, a small chemical compound that specifically inhibits protein phosphatase 1(PP1)-GADD34 phosphatase activity, increased the levels of p-eIF2␣ and ameliorated hypomyelination and oligodendrocyte loss in cultured hippocampal slices exposed to IFN-␥. Thus, our data provide evidence that an enhanced integrated stress response could promote oligodendrocyte survival in immune-mediated demyelination diseases. (Am J Pathol 2008, 173

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“…The ACR mice and the hGFAP-tTA mice have been previously described (Casper and McCarthy, 2006;Lin et al, 2004;Pascual et al, 2005). ROSA26R were obtained from Jackson Laboratories.…”

Section: Generation Of Transgenic Micementioning

confidence: 99%

Characterization of astrocyte‐specific conditional knockouts

Casper

Jones

McCarthy

2007

Genesis

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Summary: Conditional gene knockouts are a very powerful tool for elucidating gene function in animal physiology and behavior. To obtain cell-specific knockouts, a promoter is utilized that drives expression of Cre recombinase specifically to the cell population of interest. We describe several transgenic lines of mice that were created in an attempt to obtain astrocyte-specific gene recombination. A 2 kb fragment from the human glial fibrillary acidic protein promoter is utilized to drive expression of inducible Cre recombinase, with both the Tet-Off and tamoxifen responsive systems. We show data obtained from crosses with two Cre reporter lines, ROSA26R and an astrocyte Cre reporter created in our laboratory, to assess the cell specificity of gene recombination. Additionally, our system is shown to successfully recombine a floxed Connexin43 locus, although recombination is not as extensive as seen in crosses with reporter lines. genesis 45:292-299, 2007. V V C 2007 Wiley-Liss, Inc.

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Interferon-γ Induced Medulloblastoma in the Developing Cerebellum

Cited by 107 publications

References 43 publications

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

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

Enhanced Integrated Stress Response Promotes Myelinating Oligodendrocyte Survival in Response to Interferon-γ

Characterization of astrocyte‐specific conditional knockouts

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