Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice

Kaplan, Daniel H.; Shankaran, Vijay; Dighe, Anand S.; Stockert, Elisabeth; Aguet, Michel; Old, Lloyd J.; Schreiber, Robert D.

doi:10.1073/pnas.95.13.7556

Cited by 1,290 publications

(1,054 citation statements)

References 31 publications

Supporting

Mentioning

955

Contrasting

Unclassified

Order By: Relevance

“…However, analysis of chemical carcinogenesis in Stat1-mutant and IFNg receptor-mutant animals revealed the existence of an IFNg-mediated tumor surveillance system that operates in immunocompetent animals (Kaplan et al, 1998). This study demonstrated that endogenously produced IFNg was required for a tumor surveillance system capable of controlling development of both chemically induced and spontaneously arising tumors.…”

Section: Stat1 Growth Control and Cancermentioning

confidence: 75%

Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice

Levy

Gilliland

2000

Oncogene

View full text Add to dashboard Cite

Section: Stat1 Growth Control and Cancermentioning

confidence: 75%

Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice

Levy

Gilliland

2000

Oncogene

View full text Add to dashboard Cite

“…Irrespective of the stimulus used, we failed to detect any differences. As p185 bcr/abl -transformed cells respond with apoptosis to interferon treatment (Grawunder et al, 1993) and interferon-g is a key factor in tumor surveillance, we tested survival in the presence of interferon-g (IFN-g; Kaplan et al, 1998;Shankaran et al, 2001 Figure 2c). Finally, the expression of bcl 2 , bcl x and bax was reasonably similar in these cell lines as was the expression of c-Jun and c-Fos, and the upstream kinases JNK1 and JNK2 ( Figure 2d).…”

Section: Resultsmentioning

confidence: 99%

JunB is a gatekeeper for B-lymphoid leukemia

et al. 2007

View full text Add to dashboard Cite

Loss of JunB has been observed in human leukemia and lymphoma, but it remains unknown, whether this loss is relevant to disease progression. Here, we investigated the consequences of JunB deficiency using Abelson-induced B-lymphoid leukemia as a model system. Mice deficient in JunB expression succumbed to Abelson-induced leukemia with increased incidence and significantly reduced latency. Similarly, bcr/abl p185-transformed JunB-deficient (junB D/D ) cells induced leukemia in RAG2 À/À mice displaying a more malignant phenotype. These observations indicated that cell intrinsic effects within the junB D/D tumor cells accounted for the accelerated leukemia development. Indeed, explantated bcr/abl p185 transformed junB D/D cells proliferated faster than the control cells. The proliferative advantage emerged slowly after the initial transformation process and was associated with increased expression levels of the cell cycle kinase cdk6 and with decreased levels of the cell cycle inhibitor p16 INK4a . These alterations were due to irreversible reprogramming of the cell, because -once established -accelerated disease induced by junB D/D cells was not reverted by re-introducing JunB. Consistent with this observation, we found that the p16 promoter was methylated. Thus, JunB functions as a gatekeeper during tumor evolution. In its absence, transformed leukemic cells acquire an enhanced proliferative capacity, which presages a more malignant disease.

show abstract

“…Although Stat1-deficient mice do not display a heightened incidence of spontaneous neoplasms, they are more sensitive to chemical induction of tumors (Kaplan et al, 1998;Levy and Gilliland, 2000). 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).…”

Section: Stat1 Is a Prosurvival Factor In Wilms' Tumormentioning

confidence: 99%

“…We observed serine-phosphorylated STAT1 in the developing rat kidney, and it may have a role in kidney development, for example, to promote progenitor cell survival before tissue vascularization. Although STAT1-deficient mice or mice expressing constitutively inactive STAT1-S727A mutant do not have a kidney phenotype (Kaplan et al, 1998;Varinou et al, 2003), probably because activated STAT3 can replace STAT1 to drive the transcription of certain genes (Qing and Stark, 2004), it may be more revealing to evaluate the renal response to overexpression of constitutively active STAT1 during metanephric differentiation or carcinogenesis.…”

Section: Stat1 Is a Prosurvival Factor In Wilms' Tumormentioning

confidence: 99%

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

et al. 2006

View full text Add to dashboard Cite

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.

show abstract

Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice

Abstract: This study demonstrates that endogenously produced interferon ␥ (IFN-␥) forms the basis of a tumor surveillance system that controls development of both chemically induced and spontaneously arising tumors in mice.

Cited by 1,290 publications

References 31 publications

Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice

Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice

JunB is a gatekeeper for B-lymphoid leukemia

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

Contact Info

Product

Resources

About