AKT induces transcriptional activity of PU.1 through phosphorylation-mediated modifications within its transactivation domain

被引:44
作者
Rieske, P [1 ]
Pongubala, JMR [1 ]
机构
[1] MCP Hahnemann Univ, Sch Med, Dept Biochem, Philadelphia, PA 19102 USA
关键词
D O I
10.1074/jbc.M007482200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Signal transduction by the antigen receptor complexes is critical for developmental progression of B-lymphocytes, which are defined by assembly and sequential expression of immunoglobulin genes, which in turn are regulated by the enhancer elements. Although proximal antigen-receptor signal transduction pathways are well defined, the precise nuclear factors targeted by these signals remained unknown. Previous studies have demonstrated that tissue-restricted transcription factors including PU.1 and PU.1 interaction partner (PIP) function synergistically with c-Fos plus c-Jun to stimulate the kappa E3'-enhancer in 3T3 cells. In this study, we demonstrate that the functional synergy between these factors is enhanced in response to mitogen-activated protein kinase kinase kinase, in 3T3 cells, where the enhancer is inactive. However in S194 plasmacytoma cells, mitogen-activated protein kinase kinase kinase was able to stimulate the activity of PU.1 but unable to induce the kappa E3'-enhancer activity. We have found that Ras-phosphoinositide 3-kinase-dependent externally regulated kinase, AKT, induces kappa E3'-enhancer activity in both pre-B and plasmacytoma cells. AKT stimulation of the kappa E3'-enhancer is primarily due to PU.1 induction and is independent of PU.1 interaction with PIP. Activation of AKT had no effect on the expression levels of PU.1 or its protein-protein interaction with PIP. Using a series of deletion constructs, we have determined that the PU.1 acid-rich (amino acids 33-74) transactivation domain is necessary for AKT-mediated induction. Substitution analyses within this region indicate that phosphorylation of Ser(41) is necessary to respond to AKT. Consistent with these studies, ligation of antigen receptors in A20 B cells mimics AKT activation of PU.1. Taken together, these results provide evidence that PU.1 is induced by AKT signal in a phosphoinositide 3-kinase-dependent manner, leading to inducible or constitutive activation of its target genes.
引用
收藏
页码:8460 / 8468
页数:9
相关论文
共 87 条
[1]   The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells [J].
Aman, MJ ;
Lamkin, TD ;
Okada, H ;
Kurosaki, T ;
Ravichandran, KS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (51) :33922-33928
[2]   NF-kappa B: Ten years after [J].
Baeuerle, PA ;
Baltimore, D .
CELL, 1996, 87 (01) :13-20
[3]   E2A PROTEINS ARE REQUIRED FOR PROPER B-CELL DEVELOPMENT AND INITIATION OF IMMUNOGLOBULIN GENE REARRANGEMENTS [J].
BAIN, G ;
MAANDAG, ECR ;
IZON, DJ ;
AMSEN, D ;
KRUISBEEK, AM ;
WEINTRAUB, BC ;
KROP, I ;
SCHLISSEL, MS ;
FEENEY, AJ ;
VANROON, M ;
VANDERVALK, M ;
TERIELE, HPJ ;
BERNS, A ;
MURRE, C .
CELL, 1994, 79 (05) :885-892
[4]   Assembly requirements of PU.1-Pip (IRF-4) activator complexes:: inhibiting function in vivo using fused dimers [J].
Brass, AL ;
Zhu, AQ ;
Singh, H .
EMBO JOURNAL, 1999, 18 (04) :977-991
[5]   Pip, a lymphoid-restricted IRF, contains regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1 [J].
Brass, AL ;
Kehrli, E ;
Eisenbeis, CF ;
Storb, U ;
Singh, H .
GENES & DEVELOPMENT, 1996, 10 (18) :2335-2347
[6]   Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor [J].
Brunet, A ;
Bonni, A ;
Zigmond, MJ ;
Lin, MZ ;
Juo, P ;
Hu, LS ;
Anderson, MJ ;
Arden, KC ;
Blenis, J ;
Greenberg, ME .
CELL, 1999, 96 (06) :857-868
[7]   NF-BETA-A, A FACTOR REQUIRED FOR MAXIMAL INTERLEUKIN-1-BETA GENE-EXPRESSION IS IDENTICAL TO THE ETS FAMILY MEMBER PU.1 - EVIDENCE FOR STRUCTURAL ALTERATION FOLLOWING LPS ACTIVATION [J].
BURAS, JA ;
REENSTRA, WR ;
FENTON, MJ .
MOLECULAR IMMUNOLOGY, 1995, 32 (08) :541-&
[8]   Regulation of cell death protease caspase-9 by phosphorylation [J].
Cardone, MH ;
Roy, N ;
Stennicke, HR ;
Salvesen, GS ;
Franke, TF ;
Stanbridge, E ;
Frisch, S ;
Reed, JC .
SCIENCE, 1998, 282 (5392) :1318-1321
[9]   The transcription factor PU.1 is involved in macrophage proliferation [J].
Celada, A ;
Borras, FE ;
Soler, C ;
Lloberas, J ;
Klemsz, M ;
vanBeveren, C ;
McKercher, S ;
Maki, RA .
JOURNAL OF EXPERIMENTAL MEDICINE, 1996, 184 (01) :61-69
[10]   AKT/PKB and other D3 phosphoinositide-regulated kinases: Kinase activation by phosphoinositide-dependent phosphorylation [J].
Chan, TO ;
Rittenhouse, SE ;
Tsichlis, PN .
ANNUAL REVIEW OF BIOCHEMISTRY, 1999, 68 :965-1014