Jun: the master regulator in healthy and cancer cells (original) (raw)
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The mammalian Jun proteins: redundancy and specificity
Oncogene, 2001
The AP-1 transcription factor is composed of a mixture of homo-and hetero-dimers formed between Jun and Fos proteins. The dierent Jun and Fos family members vary signi®cantly in their relative abundance and their interactions with additional proteins generating a complex network of transcriptional regulators. Thus, the functional activity of AP-1 in any given cell depends on the relative amount of speci®c Jun/Fos proteins which are expressed, as well as other potential interacting proteins. This diversity of AP-1 components has complicated our understanding of AP-1 function and resulted in a paucity of information about the precise role of individual AP-1 members in distinct cellular processes. We shall discuss recent studies which suggest that dierent Jun and Fos family members may have both opposite and overlapping functions in cellular proliferation and cell fate.
Role and function of c-Jun pRotein complex in canceR cell behavioR
Transcription factors play a crucial role in the regulation of cell behavior by modulating gene expression profiles. Previous studies have described a dual role for the AP-1 family transcription factor c-Jun in the regulation of cellular fate. In various cell types weak and transient activations of c-Jun N-terminal kinase (JNK) and c-Jun appear to contribute to proliferation and survival, whereas strong and prolonged activation of JNK and c-Jun result in apoptosis. These opposite roles played by c-Jun are cell type specific and the molecular mechanisms defining these antonymous c-Jun-mediated responses remain incompletely understood.
V-Jun is a Transcriptional Activator, but Not in All Cell-Lines
Nucleic Acids Research, 1988
The recently isolated v-jun oncogene encodes a protein with sequence homology to the transcription factor AP1, as well as a similar DNA binding specificity. We show, by expressing v-jun in F9 embryocarcinoma cells, that v-jun is also a transcriptional activator. However, v-jun expression does not activate transcription in several other cell-lines, suggesting that cellspecific factors are required for v-jun activity.
Targeting c-Jun and JunB proteins as potential anticancer cell therapy
Oncogene, 2008
The activating protein-1 transcription factor, in particular the Jun proteins play critical roles in the regulation of cell proliferation and tumor progression. To study the potential clinical relevance of interfering with JunB expression, we generated retroviruses expressing short hairpin RNA. Reduction of JunB levels causes increased proliferation and tumorigenicity in wild-type murine fibroblasts, whereas in c-Jun knockout cells p53-independent cell cycle arrest and apoptosis are induced. Using melanoma-derived B16-F10 cancer cells the combination of JunB knockdown and c-Jun/JNK inactivation leads to cell cycle arrest and apoptosis-inducing factor-dependent apoptosis. Furthermore, the combined treatment extends survival of mice inoculated with the tumor cells. These results indicate that in the absence of c-Jun, JunB can act as a tumor promoter and inactivation of both, c-Jun and JunB, could provide a valuable strategy for antitumor intervention.
JunD Protects Cells from p53Dependent Senescence and Apoptosis
Molecular Cell, 2000
A fundamental issue is whether distinct functions exist Pasteur Institute Paris for each of the Jun proteins. JunD differs markedly from the c-jun and junB genes, both of which behave as France ‡ Research Institute of Molecular Pathology immediate-early genes whose expression is transiently increased upon mitogenic stimulation (Kovary and Bravo, Vienna Austria 1991a; Pfarr et al., 1994; Lallemand et al., 1997). Overexpression of JunD in immortalized fibroblasts caused slower proliferation and accumulation of cells in G1 phase, suggesting that JunD acts as a negative regulator Summary of cell growth (Pfarr et al., 1994). In contrast, c-Jun overexpression increased S phase entry, and inhibition of JunD is the most broadly expressed member of the Jun family and the AP-1 transcription factor complex. c-Jun function led to a proliferative block (Kovary and Bravo, 1991b; Pfarr et al., 1994; Wisdom et al., 1999). Primary fibroblasts lacking JunD displayed p53-dependent growth arrest, upregulated p19 Arf expression, and These results imply that cellular responses may be controlled by apparently opposing effects of different Jun premature senescence. In contrast, immortalized cell lines lacking JunD showed increased proliferation and members. Further support for such antagonistic balance between Jun members came from studying their roles in higher cyclinD1 levels. These properties are reminiscent of the effects of oncogenic Ras expression on transformation; Ras-transformed fibroblasts contained decreased JunD levels and increased c-Jun. Further-primary and established cell cultures. Furthermore, JunD Ϫ/Ϫ fibroblasts exhibited increased p53-depen-more, JunD overexpression could partially reverse the transformed phenotype, whereas c-Jun cooperates with dent apoptosis upon ultraviolet irradiation and were sensitive to the cytotoxic effects of TNF-␣. The anti-Ras and is essential for its transforming activity (Pfarr et al., 1994; Johnson et al., 1996; Mechta et al., 1997). apoptotic role of JunD was confirmed using an in vivo model of TNF-mediated hepatitis. We propose that The ras oncogene plays a central role in signaling proliferation and transformation, and Ras signaling is JunD protects cells from senescence, or apoptotic responses to stress stimuli, by acting as a modulator linked to the cell cycle machinery via induction of cyclinD1 and regulation of the Rb protein (Peeper et of the signaling pathways that link Ras to p53. al., 1997). The cyclinD1 promoter is a target for AP-1 regulation, explaining how changes in AP-1 composition Introduction may partially mimic the proliferative effects of activated Ras (Herber et al., 1994; Mechta et al., 1997; Bakiri et al., Cells can respond to changes in the extracellular environment and stress by altering the program of gene 2000). Indeed, loss of cyclinD1 expression contributes to the cell cycle block of fibroblasts lacking c-Jun (Wisdom expression. Hence, transcriptional regulators lie at the heart of interpreting extracellular signals and initiating et al., 1999). Furthermore, differences in the transcriptional activities of c-Jun and JunD explain how they can the cellular response. The AP-1 transcription factor serves as a paradigm for understanding how cyto-differentially induce cyclinD1 expression, with antagonistic effects on proliferation (Bakiri et al., 2000). Trans-plasmic signaling cascades are translated into cellular life or death decisions (Angel and Karin, 1991; Karin et formation by Ras requires cooperation with other oncogenic events, such as c-Myc overexpression, or loss al., 1997). The AP-1 complex is composed of dimers of the Jun and Fos protooncogene families that recognize of the tumor suppressor p53. In contrast, expression of activated Ras alone in primary fibroblasts causes growth the DNA motif 5Ј-TGAG/CTCA-3Ј found in many gene promoters. There are three mammalian Jun proteins arrest and senescence, which is p53/p16 dependent (Serrano et al., 1997). A similar scenario was caused by (JunD, c-Jun, and JunB) that can form Jun-Jun dimers or heterodimers with Fos proteins (c-Fos, FosB, Fra-1, aberrant expression of other oncogenic proteins such as c-Myc, E1a, or components of MAPK pathways (Ser-or Fra-2) or certain ATF partners (Angel and Karin, 1991). It was postulated that the combination of different di-rano et al., 1997; Lin et al., 1998; Prendergast, 1999). This model links the Rb and p53 pathways through an mers determines the nature of AP-1-mediated cellular responses. The jun genes and Jun proteins are distinctly important safeguard mechanism that responds to unregulated oncogenic signaling. regulated by multiple stimuli, providing the cell with a flexible battery of potential AP-1-related outcomes. Additional studies have shown that aberrant activation of several oncoproteins can initiate an apoptotic Stimuli that regulate AP-1 activity include mitogenic suicide program. Well-characterized examples include growth factors, cytokines, oxidative stress, and UV irrac-Myc and Ras (Prendergast, 1999). Oncogenic activation can also sensitize cells to death-inducing agents § To whom correspondence should be addressed (e-mail: yaniv@ pasteur.fr). such as tumor necrosis factor-␣ (TNF-␣) (Trent et al.,
Genes & Development, 1992
Bovine papillomavirus transgenic mice develop skin tumors arising from dermal fibroblasts in a process comprised of three distinctive stages: mild and aggressive fibromatoses, and fibrosarcoma. In both tissue biopsies and derivative cell lines, the proto-oncogenes junB and c-jun are induced in the latter two stages, in contrast to junD and fos. Fibrosarcoma cell lines have increased AP-1 DNA-binding activity. Overexpression of junB or c-jun by transfection into the mild fibromatosis stage elicited changes in cell shape and anchorage independence, whereas junD did not. Similar transfections of normal skin fibroblasts had no effect. Thus, junB and c-jun represent progression factors whose activities are necessary at an intermediate stage of tumor development, subsequent to the initiation of aberrant proliferation.