Accumulation of fra-1 in ras-transformed cells depends on both transcriptional autoregulation and MEK-dependent posttranslational stabilization

被引:90
作者
Casalino, L [1 ]
De Cesare, D [1 ]
Verde, P [1 ]
机构
[1] CNR, Inst Genet & Biophys A Buzzati Traverso, I-80125 Naples, Italy
关键词
D O I
10.1128/MCB.23.12.4401-4415.2003
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
The AP-1 transcription factor plays an essential role in cell proliferation and tumorigenesis. It was previously shown that the fra-1 gene product is upregulated by various oncogenes and is involved in the in vitro and in vivo transformation of thyroid cells. Here we show that the ras oncogene-dependent accumulation of Fra-1 is mediated by a positive feedback mechanism which requires both transcriptional autoregulation and post-translational stabilization of the protein. The oncogene-dependent transcriptional activation involves the cooperation between both Raf-dependent and Raf-independent pathways and is mediated by an AP-1 site within the fra-1 first intron, which becomes stably occupied by a transcriptionally active Fra-1-containing complex in ras-transformed cells. The posttranslational stabilization results in a drastic increase in the Fra-1 half-life in ras-transformed cells and is totally dependent on the activity of the MEK/ERK phosphorylation pathway. The analysis of the Fra-1 transactivation potential shows that the protein is able to stimulate a heterologous promoter in a ras-dependent manner, but the transactivating activity requires the recruitment of a heterodimeric partner. These data show that the alteration of multiple regulatory mechanisms is required for the constitutive activation of Fra-1 as a nuclear target of ras transformation.
引用
收藏
页码:4401 / 4415
页数:15
相关论文
共 65 条
  • [1] The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor
    Ambartsumian, N
    Klingelhöfer, J
    Grigorian, M
    Christensen, C
    Kriajevska, M
    Tulchinsky, E
    Georgiev, G
    Berezin, V
    Bock, E
    Rygaard, J
    Cao, RH
    Cao, YH
    Lukanidin, E
    [J]. ONCOGENE, 2001, 20 (34) : 4685 - 4695
  • [2] CULTURE OF HORMONE-DEPENDENT FUNCTIONAL EPITHELIAL-CELLS FROM RAT THYROIDS
    AMBESIIMPIOMBATO, FS
    PARKS, LAM
    COON, HG
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1980, 77 (06): : 3455 - 3459
  • [3] The ability of Fos family members to produce phenotypic changes in epithelioid cells is not directly linked to their transactivation potentials
    Andersen, H
    Mahmood, S
    Tkach, V
    Cohn, M
    Kustikova, O
    Grigorian, M
    Berezin, V
    Bock, E
    Lukanidin, E
    Tulchinsky, E
    [J]. ONCOGENE, 2002, 21 (31) : 4843 - 4848
  • [4] The plasminogen activation system in tumor growth, invasion, and metastasis
    Andreasen, PA
    Egelund, R
    Petersen, HH
    [J]. CELLULAR AND MOLECULAR LIFE SCIENCES, 2000, 57 (01) : 25 - 40
  • [5] Function and regulation of AP-1 subunits in skin physiology and pathology
    Angel, P
    Szabowski, A
    Schorpp-Kistner, M
    [J]. ONCOGENE, 2001, 20 (19) : 2413 - 2423
  • [6] Cell cycle-dependent variations in c-Jun and JunB phosphorylation: a role in the control of cyclin D1 expression
    Bakiri, L
    Lallemand, D
    Bossy-Wetzel, E
    Yaniv, M
    [J]. EMBO JOURNAL, 2000, 19 (09) : 2056 - 2068
  • [7] Promoter specificity and biological activity of tethered AP-1 dimers
    Bakiri, L
    Matsuo, K
    Wisniewska, M
    Wagner, EF
    Yaniv, M
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (13) : 4952 - 4964
  • [8] Increase in AP-1 activity is a general event in thyroid cell transformation in vitro and in vivo
    Battista, S
    de Nigris, F
    Fedele, M
    Chiappetta, G
    Scala, S
    Vallone, D
    Pierantoni, GM
    Megar, T
    Santoro, M
    Viglietto, G
    Verde, P
    Fusco, A
    [J]. ONCOGENE, 1998, 17 (03) : 377 - 385
  • [9] Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation
    Behrens, A
    Jochum, W
    Sibilia, M
    Wagner, EF
    [J]. ONCOGENE, 2000, 19 (22) : 2657 - 2663
  • [10] BERGERS G, 1995, MOL CELL BIOL, V15, P3748