Tumor suppression by IFN regulatory factor-1 is mediated by transcriptional down-regulation of cyclin D1.
IFNs have been ascribed to mediate antitumor effects. IFN regulatory factor-1 (IRF-1) is a major target gene of IFNs. It inhibits cell proliferation and oncogenic transformation. Here, we show that 60% of all mRNAs deregulated by oncogenic transformation mediated by c-myc and H-ras are reverted to the expression levels of nontransformed cells by IRF-1. These include cell cycle-regulating genes. An indirect target is cyclin D1. Activation of IRF-1 decreased cyclin D1 expression and cyclin-dependent kinase 4 kinase activity concomitant with change in the levels of hyperphosphorylated retinoblastoma protein. These effects are mediated by inhibition of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway and a transcriptional repression of cyclin D1. As shown by in vitro assays and tumor growth in nude mice, IRF-1-mediated effects on cell cycle progression were found to be overridden by ectopic expression of cyclin D1. Conversely, decrease of cyclin D1 by RNA interference experiments prevents transformation and tumor growth. The data show that cyclin D1 is a key target for IRF-1-mediated tumor-suppressive effects.
Kröger
Andrea
A
Department of Gene Regulation and Differentiation, Helmholtz Center for Infection Research, Braunschweig, Germany. andrea.kroger@helmholtz-hzi.de
Stirnweiss
Anja
A
Pulverer
Julia Elisabeth
JE
Klages
Katjana
K
Grashoff
Martina
M
Reimann
Jörg
J
Hauser
Hansjörg
H
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D011905:Genes, ras; D050856:Interferon Regulatory Factor-1 / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
D050856:Interferon Regulatory Factor-1; D012333:RNA, Messenger; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4