Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma - PubMed (original) (raw)

Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma

J F Bromberg et al. Proc Natl Acad Sci U S A. 1996.

Abstract

Type I (alpha, beta) and type II (gamma) interferons (IFNs) can restrict the growth of many cell types. INF-stimulated gene transcription, a key early event in IFN response, acts through the Janus kinase-signal transducers and activators of transcription pathway, in which both IFN-alpha and IFN-gamma activate the transcription factor Stat1. A cell line lacking Stat1 (U3A) was not growth-arrested by IFN-alpha or IFN-gamma, and experiments were carried out with U3A cells permanently expressing normal or various mutant forms of Stat1 protein. Only cells in which complete Stat1 activity was available (Stat1alpha) were growth-inhibited by IFN-gamma. A mutant that supports 20-30% normal transcription did not cause growth restraint. In contrast, IFN-alpha growth restraint was imposed by cells producing Stat1beta, which lacks transcriptional activation potential. This parallels earlier results showing the truncated Stat1 can function in IFN-alpha gene activation. In addition to experiments on long-term cultured cells, we also found that wild-type primary mouse embryonic fibroblasts were inhibited by IFNs, but fibroblasts from Stat1-deficient mouse embryos were not inhibited by IFNs.

PubMed Disclaimer

Cited by

INFα-2b inhibitory effects on CD4(+)CD25(+)FOXP3(+) regulatory T cells in the tumor microenvironment of C57BL/6 J mice with melanoma xenografts.
Yu Y, Huang R, Zong X, He X, Mo W. Yu Y, et al. BMC Cancer. 2016 Jul 7;16:397. doi: 10.1186/s12885-016-2473-0. BMC Cancer. 2016. PMID: 27389040 Free PMC article.
BRCA1 transcriptionally regulates genes involved in breast tumorigenesis.
Welcsh PL, Lee MK, Gonzalez-Hernandez RM, Black DJ, Mahadevappa M, Swisher EM, Warrington JA, King MC. Welcsh PL, et al. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7560-5. doi: 10.1073/pnas.062181799. Proc Natl Acad Sci U S A. 2002. PMID: 12032322 Free PMC article.
Interferon-alpha2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism.
Romerio F, Riva A, Zella D. Romerio F, et al. Br J Cancer. 2000 Aug;83(4):532-8. doi: 10.1054/bjoc.2000.1263. Br J Cancer. 2000. PMID: 10945503 Free PMC article.
Phosphorylation of the Stat1 transactivating domain is required for the response to type I interferons.
Pilz A, Ramsauer K, Heidari H, Leitges M, Kovarik P, Decker T. Pilz A, et al. EMBO Rep. 2003 Apr;4(4):368-73. doi: 10.1038/sj.embor.embor802. Epub 2003 Mar 21. EMBO Rep. 2003. PMID: 12671680 Free PMC article.
Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway.
Kovarik P, Stoiber D, Eyers PA, Menghini R, Neininger A, Gaestel M, Cohen P, Decker T. Kovarik P, et al. Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13956-61. doi: 10.1073/pnas.96.24.13956. Proc Natl Acad Sci U S A. 1999. PMID: 10570180 Free PMC article.

References

1. J Virol. 1996 Jan;70(1):647-50 - PubMed
1. Ann N Y Acad Sci. 1995 Jun 30;758:331-8 - PubMed
1. Nucleic Acids Res. 1995 Feb 11;23(3):459-63 - PubMed
1. Genes Dev. 1994 Jan;8(1):9-22 - PubMed
1. Science. 1994 Jun 3;264(5164):1415-21 - PubMed

Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma - PubMed (original) (raw)