High level class II trans-activator induction does not occur with transient activation of the IFN-γ signaling pathway

被引:18
作者
Eason, DD
Blanck, G
机构
[1] Univ S Florida, Coll Med, Dept Biochem & Mol Biol, Tampa, FL 33612 USA
[2] Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Program Immunol, Tampa, FL 33612 USA
关键词
D O I
10.4049/jimmunol.166.2.1041
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Gene activation in early development is highly dependent on precise concentrations of trans-acting factors for the activation of different genes at differing points in the embryo. Thus, not only is the presence or absence of a particular trans-activator or repressor relevant in determining gene activation, but also the concentration of the regulatory protein must be above or below a certain threshold for proper gene regulation. Signaling pathways in somatic cells are thought to represent cascades of on/off switches, mediated most commonly by phosphorylation, Here we demonstrate a quantitative mechanism for regulating the level of a component of the IFN-gamma signaling pathway that in effect represents the differential sensitivities of STAT1, IFN-regulatory factor-1, and class II trans-activator (CIITA) to IFN-gamma. Unlike developmental gene regulation, in which specificity of gene activation is a function of regulatory protein concentrations, specificity of gene activation in the IFN-gamma signaling pathway is regulated by the duration of the activation of the primary IFN-gamma -regulatory protein, STAT1. This result most likely explains previously reported data indicating that a minimum amount of IFN-gamma is required for MHC class II gene activation despite the fact that the level of the IFN-gamma -inducible factor directly required for MHC class II induction, CIITA, directly correlates with the level of MHC class II expression. The induction of a high level of CIITA is dependent on sustained IFN-gamma signaling. The possible implications of this result for tumorigenesis are discussed.
引用
收藏
页码:1041 / 1048
页数:8
相关论文
共 51 条
[1]   GROWTH-FACTORS AND CANCER [J].
AARONSON, SA .
SCIENCE, 1991, 254 (5035) :1146-1153
[2]   Unresponsiveness to interferon associated with STAT1 protein deficiency in a gastric adenocarcinoma cell line [J].
Abril, E ;
Real, LM ;
Serrano, A ;
Jimenez, P ;
García, A ;
Canton, J ;
Trigo, I ;
Garrido, F ;
Ruiz-Cabello, F .
CANCER IMMUNOLOGY IMMUNOTHERAPY, 1998, 47 (02) :113-120
[3]   ROLE OF MHC GENE-PRODUCTS IN IMMUNE REGULATION [J].
BENACERRAF, B .
SCIENCE, 1981, 212 (4500) :1229-1238
[4]   Emergent properties of networks of biological signaling pathways [J].
Bhalla, US ;
Iyengar, R .
SCIENCE, 1999, 283 (5400) :381-387
[5]   GAMMA-INTERFERON INDUCTION OF HLA CLASS-II MESSENGER-RNAS IN DERMAL FIBROBLASTS STUDIED BY RNASE PROTECTION ANALYSIS [J].
BLANCK, G ;
LOK, M ;
KOK, K ;
DOWNIE, E ;
KORN, JH ;
STROMINGER, JL .
HUMAN IMMUNOLOGY, 1990, 29 (02) :150-156
[6]   Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling [J].
Briscoe, J ;
Sussel, L ;
Serup, P ;
Hartigan-O'Connor, D ;
Jessell, TM ;
Rubenstein, JLR ;
Ericson, J .
NATURE, 1999, 398 (6728) :622-627
[7]   Cytotoxic response of ovarian cancer cell lines to IFN-γ is associated with sustained induction of IRF-1 and p21 mRNA [J].
Burke, F ;
Smith, PD ;
Crompton, MR ;
Upton, C ;
Balkwill, FR .
BRITISH JOURNAL OF CANCER, 1999, 80 (08) :1236-1244
[8]  
CELADA A, 1987, J IMMUNOL, V139, P147
[9]  
Dong YS, 1999, J IMMUNOL, V162, P4731
[10]  
EASON DD, 2000, THESIS U S FLORIDA T