FOXO transcription factors cooperate with δEF1 to activate growth suppressive genes in B lymphocytes

被引:70
作者
Chen, Jing
Yusuf, Isharat
Andersen, Hilde-Marie
Fruman, David A. [1 ]
机构
[1] Univ Calif Irvine, Ctr Immunol, Irvine, CA 92697 USA
[2] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA
关键词
D O I
10.4049/jimmunol.176.5.2711
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Forkhead transcription factors regulate many aspects of lymphocyte development and function. The FOXO subgroup of Forkhead factors opposes proliferation and survival, and FOXO inactivation is an important outcome of Ag receptor signaling. FOXO activity at target promoters is modulated by other transcription factors in a manner dependent on cell type and external stimulus. We have investigated the mechanisms by which FOXO proteins activate the promoters of two target genes in murine B lymphocytes, Ccng2 (encoding cyclin G,) and Rbl2 (p130), each of which has been implicated in cell cycle arrest. FOXO proteins bound directly to both promoters in vitro and in vivo, augmented transcriptional activity in reporter assays, and increased expression of the endogenous genes. Each of the promoter sequences has consensus binding sites for the delta EF1 transcription factor, previously shown to either repress or activate different promoters. delta EF1 bound to the Ccng2 and Rbl2 promoters in vitro and in vivo and increased reporter activity as well as endogenous mRNA levels for these genes. Strikingly, delta EF1 synergized with FOXO proteins to strongly activate transcription from both promoters. Coexpression of delta EF1 enhanced FOXO-induced cell cycle arrest in B lymphoma cells. These findings establish a novel mechanism of FOXO function at target promoters: cooperation with delta EF1.
引用
收藏
页码:2711 / 2721
页数:11
相关论文
共 34 条
[11]   Phosphorylation-dependent and -independent functions of p130 cooperate to evoke a sustained G1 block [J].
Hansen, K ;
Farkas, T ;
Lukas, J ;
Holm, K ;
Rönnstrand, L ;
Bartek, J .
EMBO JOURNAL, 2001, 20 (03) :422-432
[12]   Impairment of T cell development in delta EF1 mutant mice [J].
Higashi, Y ;
Moribe, H ;
Takagi, T ;
Sekido, R ;
Kawakami, K ;
Kikutani, H ;
Kondoh, H .
JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 185 (08) :1467-1479
[13]   Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification [J].
Hosaka, T ;
Biggs, WH ;
Tieu, D ;
Boyer, AD ;
Varki, NM ;
Cavenee, WK ;
Arden, KC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (09) :2975-2980
[14]   Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells [J].
Kharas, MG ;
Deane, JA ;
Wong, S ;
O'Bosky, KR ;
Rosenberg, N ;
Witte, ON ;
Fruman, DA .
BLOOD, 2004, 103 (11) :4268-4275
[15]   Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress [J].
Kops, GJPL ;
Dansen, TB ;
Polderman, PE ;
Saarloos, I ;
Wirtz, KWA ;
Coffer, PJ ;
Huang, TT ;
Bos, JL ;
Medema, RH ;
Burgering, BMT .
NATURE, 2002, 419 (6904) :316-321
[16]   Control of cell cycle exit and entry by protein kinase B-regulated Forkhead transcription factors [J].
Kops, GJPL ;
Medema, RH ;
Glassford, J ;
Essers, MAG ;
Dijkers, PF ;
Coffer, PJ ;
Lam, EWF ;
Burgering, BMT .
MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (07) :2025-2036
[17]   DAF-16 target genes that control C-elegans life-span and metabolism [J].
Lee, SS ;
Kennedy, S ;
Tolonen, AC ;
Ruvkun, G .
SCIENCE, 2003, 300 (5619) :644-647
[18]   Regulation of NF-κB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a [J].
Lin, L ;
Hron, JD ;
Peng, SL .
IMMUNITY, 2004, 21 (02) :203-213
[19]   Control of cyclin G2 mRNA expression by forkhead transcription factors:: Novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkhead [J].
Martínez-Gac, L ;
Marqués, M ;
García, Z ;
Campanero, MR ;
Carrera, AC .
MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (05) :2181-2189
[20]   Differential regulation of c-Myb-induced transcription activation by a phosphorylation site in the negative regulatory domain [J].
Miglarese, MR ;
Richardson, AF ;
Aziz, N ;
Bender, TP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (37) :22697-22705