Cytoplasmic c‐Fos induced by the YXXQ‐derived STAT3 signal requires the co‐operative MEK/ERK signal for its nuclear translocation

Background:The oncoprotein HBXIP acts as a coactivator of transcription factor in cancer. Results: The nuclear import of HBXIP depends on interacting with c-Fos and ATM-mediated phosphorylation of HBXIP and p-ERK1/2-mediated phosphorylation of c-Fos. Conclusion: The nuclear import of HBXIP is required for collaboration with c-Fos. Significance: We provide new insights into the mechanism that HBXIP imports into the nucleus in breast cancer cells.

Section: Discussionmentioning

confidence: 57%

Section: Hepatitis B X-interacting Protein (Hbxip)mentioning

confidence: 99%

See 1 more Smart Citation

The Nuclear Import of Oncoprotein Hepatitis B X-interacting Protein Depends on Interacting with c-Fos and Phosphorylation of Both Proteins in Breast Cancer Cells

Zhang

Zhao

et al. 2013

“…In particular, transcriptional activity can be enhanced via phosphorylation of various serines and threonines that may also participate in protein stabilization. The kinases include the MAPK p38, ERK1/2, and ERK5 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), where the role of ERK5 is disputed (26), as well as the ERK1/2-activated kinases Rsk1/2 (12,14,16,22) and IB kinase (27). In contrast, c-Fos can be transcriptionally repressed by sumoylation at a specific lysine (28,29).…”

mentioning

confidence: 99%

Heterodimerization with Different Jun Proteins Controls c-Fos Intranuclear Dynamics and Distribution

Malnou

Brockly

Favard

et al. 2010

The c-Fos proto-oncogenic transcription factor defines a multigene family controlling many processes both at the cell and the whole organism level. To bind to its target AP-1/12-O-tetradecanoylphorbol-13-acetate-responsive element or cAMPresponsive element DNA sequences in gene promoters and exert its transcriptional part, c-Fos must heterodimerize with other bZip proteins, its best studied partners being the Jun proteins (c-Jun, JunB, and JunD). c-Fos expression is regulated at many transcriptional and post-transcriptional levels, yet little is known on how its localization is dynamically regulated in the cell. Here we have investigated its intranuclear mobility using fluorescence recovery after photobleaching, genetic, and biochemical approaches. The AP-1 transcriptional complex comprises a large family of dimeric transcription factors involved in the control of numerous physiological and pathological processes. These include among others cell proliferation, differentiation, apoptosis, responses to environmental cues, tumorigenesis, developmental defects, and immune diseases (1-5). Its best studied components are the Fos (c-Fos, Fra-1, Fra-2, and FosB) and Jun (c-Jun, JunB, and JunD) family proteins, all of which necessitate dimerization via a leucine zipper (LZ) 5 to acquire transcriptional competence. Fos proteins can only heterodimerize with other AP-1 components, whereas Jun proteins can also homodimerize, even though heterodimerization with any of the Fos is favored (6, 7). Thanks to both the LZ and the adjacent basic DNA-binding domains (DBD), Fos⅐Jun AP-1 dimers bind defined DNA sequences known as 12-O-tetradecanoylphorbol-13-acetate-responsive elements (TREs) and less well to cAMPresponsive elements (CREs) that are found in many gene promoters, explaining the diversity of AP-1 effects. Importantly, AP-1 can act as a positive or a negative transcriptional regulator depending on its composition, the target gene, the cell context, the extracellular environment, and which intracellular signaling cascades are activated (2, 6).c-Fos is the first discovered and best studied member of the Fos family (8, 9). It is constitutively expressed in a limited number of tissues but is rapidly and transiently induced in many other cell types by a large variety of stimuli (9). In the latter case, c-Fos accumulation is controlled at the level of transcription, mRNA turnover, and protein stability (8, 10, 11). Moreover, c-Fos intracellular localization (see below) and transcriptional activity are tightly regulated (8). In particular, transcriptional activity can be enhanced via phosphorylation of various serines and threonines that may also participate in protein stabilization. The kinases include the MAPK p38, ERK1/2, and ERK5 * This work was supported by grants from the ARC, Association pour la Recherche sur le Cancer, the Agence Nationale de Recherches (ANR-08-BLAN-007-01), the French Ligue Nationale Contre le Cancer, and by the CNRS.

“…After translation, c-Fos accumulates in the nucleus very rapidly. Its nuclear import appears to be regulated by extracellular signals, as newly synthesized c-Fos accumulates in the cytoplasm in serum-deprived cells (21,22). Different regions in the c-Fos protein are required for its efficient nuclear import (23,24).…”

mentioning

confidence: 99%

Transportin Is a Major Nuclear Import Receptor for c-Fos

Arnold¹,

Nath²,

Wohlwend

et al. 2006

c-Fos, a component of the transcription factor AP-1, is rapidly imported into the nucleus after translation. We established an in vitro system using digitonin-permeabilized cells to analyze nuclear import of c-Fos in detail. Two import receptors of the importin ␤ superfamily, importin ␤ itself and transportin, promote import of c-Fos in vitro. Under conditions where importin ␤-dependent transport was blocked, c-Fos still accumulated in the nucleus in the presence of cytosol. Inhibition of the transportin-dependent pathway, in contrast, abolished import of c-Fos. Furthermore, c-Fos mutants that interact with transportin but not with importin ␤ were efficiently imported in the presence of cytosol. Hence, transportin appears to be the predominant import receptor for c-Fos. A detailed biochemical characterization revealed that the interaction of transportin with c-Fos is distinct from the interaction with its established import cargoes, the M9 sequence of heterogeneous nuclear ribonucleoprotein A1 or the nuclear localization sequence of some basic proteins. Likewise, the binding sites on importin ␤ for its classic import cargo and for c-Fos can be separated. In summary, c-Fos employs a novel mode of receptor-cargo interaction. Hence, transportin may be as versatile as importin ␤ in recognizing different nuclear import cargoes.Import of proteins into the nucleus is mediated by importins, members of the importin ␤ superfamily. The "classic" signals for nuclear import (nuclear localization signal; NLS) 2 are short basic stretches of amino acids with lysines as characteristic components, which may occur either as a single or a bipartite motif. These classic NLSs are recognized by the adapter molecule importin ␣, which forms a heterodimer with the actual transport receptor, importin ␤ (for reviews see Refs. 1-3). The importin ␣/␤-NLS-cargo complex is then translocated through the nuclear pore complex. Nucleoporins, the protein components of the nuclear pore complex, may interact with the transport receptor, facilitating the translocation of the complex. Importin ␤ interaction with RanGTP on the nuclear side of the nuclear pore complex results in dissociation of the transport complex (4). Hundreds of individual nuclear proteins or proteins that shuttle between the nucleus and the cytoplasm are thought to use this classic importin ␣/␤ nuclear import pathway. Over the last couple of years, however, a number of proteins have been described that do not depend on the adapter protein importin ␣. Some of these bind directly to the classic import receptor, importin ␤, without requiring any adapter protein. These include the proteins Rev and Rex of the human immunodeficiency virus (5, 6) and the human T-cell leukemia virus (7), respectively, the T-cell protein tyrosine phosphatase (8), the parathyroid hormone-related protein (PTHrP) (9), cyclin B1 (10), the sterol regulatory element-binding protein 2 (SREBP-2 (11)), the zinc finger protein Snail (12), and the transcription factor CREB (13). Many of these proteins also contain basi...