Y box-binding protein 1 induces resistance to oncogenic transformation by the phosphatidylinositol 3-kinase pathway

被引:55
作者
Bader, AG
Feits, KA
Jiang, N
Chang, HW
Vogt, PK
机构
[1] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA
[2] Digital Gene Technol Inc, La Jolla, CA 92037 USA
关键词
Akt; p3k; cell transformation; TOR;
D O I
10.1073/pnas.2135336100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Y box-binding protein 1 (YB-1) is a multifunctional protein that can act as a regulator of transcription and of translation. In chicken embryo fibroblasts transformed by the oncoproteins P3k (phosphatidylinositol 3-kinase) or Akt, YB-1 is transcriptionally downregulated. Expression of YB-1 from a retroviral vector induces a strong cellular resistance to transformation by P3k or Akt but does not affect sensitivity to transformation by other oncoproteins, such as Src, Jun, or Qin. The YB-1-expressing cells assume a tightly adherent, flat phenotype, with YB-1 localized in the cytoplasm, and show a greatly reduced saturation density. Both cap-dependent and cap-independent translation is inhibited in these cells, but the activity of Akt remains unaffected, suggesting that YB-1 functions downstream of Akt. A YB-1 protein with a loss-of-function mutation in the RNA-binding motif no longer binds to the mRNA cap structure, is localized in the cell nucleus, does not induce the flat cellular phenotype, and fails to interfere with P3k- or Akt-induced oncogenic transformation. This mutant also does not inhibit cap-dependent or cap-independent translation. These results suggest that YB-1 acts like a rapamycin mimic, inhibiting translational events that are required in phosphatidylinositol 3-kinase-driven oncogenic transformation.
引用
收藏
页码:12384 / 12389
页数:6
相关论文
共 63 条
[1]   The role of PI 3-kinase in insulin action [J].
Alessi, DR ;
Downes, CP .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 1998, 1436 (1-2) :151-164
[2]   The Akt kinase:: Molecular determinants of oncogenicity [J].
Aoki, M ;
Batista, O ;
Bellacosa, A ;
Tsichlis, P ;
Vogt, PK .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (25) :14950-14955
[3]   A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt [J].
Aoki, M ;
Blazek, E ;
Vogt, PK .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (01) :136-141
[4]   The catalytic subunit of phosphoinositide 3-kinase: Requirements for oncogenicity [J].
Aoki, M ;
Schetter, C ;
Himly, M ;
Batista, O ;
Chang, HW ;
Vogt, PK .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (09) :6267-6275
[5]   TOJ3, a target of the v-jun transcription factor, encodes a protein with transforming activity related to human microspherule protein 1 (MCRS1) [J].
Bader, AG ;
Schneider, ML ;
Bister, K ;
Hartl, M .
ONCOGENE, 2001, 20 (51) :7524-7535
[6]   Prolactin and insulin synergize to regulate the translation modulator PHAS-I via mitogen-activated protein kinase-independent but wortmannin- and rapamycin-sensitive pathway [J].
Barash, I .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 1999, 155 (1-2) :37-49
[7]   CHARACTERIZATION OF ASSOCIATION OF SPECIFIC PROTEINS WITH MESSENGER RIBONUCLEIC-ACID [J].
BARRIEUX, A ;
INGRAHAM, HA ;
NYSTUL, S ;
ROSENFELD, MG .
BIOCHEMISTRY, 1976, 15 (16) :3523-3528
[8]   A RETROVIRAL ONCOGENE, AKT, ENCODING A SERINE-THREONINE KINASE CONTAINING AN SH2-LIKE REGION [J].
BELLACOSA, A ;
TESTA, JR ;
STAAL, SP ;
TSICHLIS, PN .
SCIENCE, 1991, 254 (5029) :274-277
[9]   PROTEIN TIGHTLY BOUND TO GLOBIN MESSENGER-RNA [J].
BLOBEL, G .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1972, 47 (01) :88-&
[10]   V-JUN ENCODES A NUCLEAR-PROTEIN WITH ENHANCER BINDING-PROPERTIES OF AP-1 [J].
BOS, TJ ;
BOHMANN, D ;
TSUCHIE, H ;
TJIAN, R ;
VOGT, PK .
CELL, 1988, 52 (05) :705-712