C/EBPβ: lost beyond translation
2011; Springer Nature; Volume: 30; Issue: 18 Linguagem: Inglês
10.1038/emboj.2011.288
ISSN1460-2075
Autores Tópico(s)RNA modifications and cancer
ResumoHave you seen?14 September 2011free access C/EBPβ: lost beyond translation Daniel S Peeper Corresponding Author Daniel S Peeper Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands Search for more papers by this author Daniel S Peeper Corresponding Author Daniel S Peeper Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands Search for more papers by this author Author Information Daniel S Peeper 1 1Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands *Correspondence to: [email protected] The EMBO Journal (2011)30:3663-3664https://doi.org/10.1038/emboj.2011.288 There is an Article (September 2011) associated with this Have you seen?. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info A/U-rich elements (AREs) are short sequences in the 3′UTRs of genes, acting in cis to regulate mRNA decay and translation. In this issue of The EMBO Journal, Basu et al (2011) describe a new function for AREs, in the context of the C/EBPβ transcription factor. Specifically, they show that the C/EBPβ ARE is responsible for sequestering the corresponding protein from subcellular compartments in which kinases reside to derepress C/EBPβ. As a result, the transcription factor is unable to execute its cytostatic function in the face of an oncogenic insult. These results reveal a new mode of regulation of an already carefully controlled transcription factor. Given the widespread occurrence of AREs in genes, they also predict that this process, termed ‘3′UTR regulation of protein activity’ (UPA), may have a more common role in controlling protein activities. The transcription factor C/EBPβ (for CCAAT/enhancer-binding protein) is involved in a plethora of physiological and pathophysiological processes, including cancer. It is a basic leucine zipper DNA-binding domain protein regulating proliferation and differentiation of a wide range of cell types. It has several relatives and through homodimerization and heterodimerization C/EBPβ can be recruited to DNA to regulate gene transcription. Consistent with its prevalent expression and diverse functions, it is regulated by a complex array of mechanisms. For example, the C/EBPβ transcript is translated into several isoforms, including a truncated form (LIP, for Liver Inhibitory Protein) and a longer polypeptide (LAP, for Liver Activating Protein). Further, the C/EBPβ messenger contains a small upstream open reading frame governing the balanced expression of C/EBPβ isoforms in response to changing protein translation conditions (Wethmar et al, 2010). Adding to this multifactorial regulation, C/EBPβ is also subject to activation from a latent form, involving auto-inhibitory elements that suppress DNA binding and transactivation (Kowenz-Leutz et al, 1994; Lee et al, 2010). A key signal for derepression can be provided by an active RAS pathway, particularly through the RAF-MEK-ERK module, thereby enhancing C/EBPβ's cytostatic function, for example, during oncogene-induced senescence (OIS; Sebastian et al, 2005; Kuilman et al, 2008). Intriguingly, there is also a pro-oncogenic role associated with this transcription factor, as conversely, C/EBPβ-deficient mice are refractory to skin tumour development driven by oncogenic RAS (Zhu et al, 2002). In this issue of The EMBO Journal, Peter Johnson and colleagues reveal yet another facet of C/EBPβ regulation, and it is a most original one (Basu et al, 2011). The investigators asked whether the 3′UTR of the C/EBPβ transcript contributes to the downregulation of its resultant protein product by oncogenic RAS, an observation they made earlier (Sebastian and Johnson, 2009). While expecting an miRNA-dependent silencing mechanism, they observed that the C/EBPβ transcript containing an intact 3′UTR displayed a compromised cytostatic activity compared with the corresponding mRNA lacking this region. As this could not be explained by differential mRNA or protein expression, Basu et al (2011) dug further and found that, unexpectedly, the 3′UTR regulated C/EBPβ function by blocking its post-translational activation. This effect was also seen for C/EBPα and was mapped to a so-called ARE (for A/U-rich element). AREs like those encoded by C/EBPβ are short cis-acting sequences that can recruit several RNA-binding proteins, including HuR. They are known to manage post-transcriptional control by regulating mRNA decay and translation (Khabar, 2010). RNAi depletion of HuR largely relieved 3′UTR inhibition of C/EBPβ, converting it into a potent growth inhibitor in the context of active RAS. The authors went on to show that the UTR was responsible for directing the C/EBPβ transcript to peripheral cytoplasmic regions, in a HuR-dependent fashion. In these subcellular compartments, C/EBPβ is sequestered from its activating kinases, such as p-ERK1/2, which reside mostly in a perinuclear region, explaining why RAS-induced phosphorylations were diminished in C/EBPβ-UTR-encoded protein (Figure 1). Correspondingly, whereas active C/EBPβ lacking the 3′UTR stimulated the senescence-associated secretome as expected (Kuilman and Peeper, 2009), the full-length messenger failed to do so. Lastly, Basu et al (2011) show that this phenomenon is specific for immortalized and oncogenically transformed cells, as primary cells with a reduced cytoplasmic HuR pool apparently abrogate the negative effects of the 3′UTR, allowing for OIS to occur. Figure 1.Model displaying a new mode of control for C/EBPβ, called 3′UTR regulation of protein activity (UPA). Previously established roles for 3′UTRs include regulation of mRNA stability (top) and mRNA translation (middle). Basu et al (2011) show, for the transcription factor C/EBPβ, that an A/U-rich element (ARE) within the 3′UTR of its messenger recruits RNA-binding proteins including HuR (bottom). HuR, and possibly other factors, direct C/EBPβ to peripheral areas in the cytoplasm, sequestering it from kinases necessary for activation. This process is operational only in neoplastic cells, presumably because untransformed cells have a reduced cytoplasmic pool of HuR. Download figure Download PowerPoint These results not only add a new dimension to C/EBPβ regulation, but also uncover a new role for 3′UTRs. In addition to their established functions in governing mRNA stability and translation, this paper suggests that 3′UTRs can also modulate the activation of the protein encoded by the corresponding transcript, a mechanism that the authors dub 3′UTR regulation of protein activity (UPA). Of course, this begs the question as to how general this mechanism is, beyond the two C/EBP family members studied here. The fact that up to 8% of human genes contain ARE-like regions (Bakheet et al, 2003) predicts that indeed many genes may be subject to this mode of post-translational control. Another question emerging from this work is how the subcellular distribution of HuR is controlled differentially in normal and cancer cells, and how it suppresses C/EBPβ activity in the latter. This is particularly interesting because of the observation that increased HuR levels can occur in human malignancies (Yuan et al, 2010). Also deserving further study is the nature and role of the peripheral cytoplasmic areas to which the 3′UTR directs the C/EBPβ messenger. For example, are they so-called ‘stress granules’ to which some mRNAs localize when exposed to shock conditions? HuR and other RNA-binding proteins are known to accumulate in these foci (von Roretz and Gallouzi, 2008). C/EBPβ is already known to be regulated at various levels, and the current paper adds yet another layer of complexity. Conceivably, this is related to the diverse functions this transcription factor has in proliferation and differentiation. In particular, the apparently opposing functions of C/EBPβ in RAS-induced senescence versus RAS-induced skin tumourigenesis may arise from the UPA mechanism. Last but not least, a typical way to study gene function is to drive expression from a UTR-less cDNA cassette. One wonders how many properties thus ascribed to genes need reevaluation, now that it is becoming increasingly clear that non-coding regions harbour critical regulatory functions controlling translation and, as shown here, post-translational activation. Conflict of Interest The author declares that he has no conflict of interest. References Bakheet T, Williams BRG, Khabar KSA (2003) ARED 2.0: an update of AU-rich element mRNA database. Nucleic Acids Res 31: 421–423CrossrefCASPubMedWeb of Science®Google Scholar Basu SK, Malik R, Huggins CJ, Lee S, Sebastian T, Sakchaisri K, Quiñones OA, Alvord WG, Johnson PF (2011) 3′UTR elements inhibit Ras-induced C/EBPβ post-translational activation and senescence in tumour cells. EMBO J 30: 3714–3728Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Khabar KSA (2010) Post-transcriptional control during chronic inflammation and cancer: a focus on AU-rich elements. 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Bioessays 32: 885–893Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Yuan Z, Sanders AJ, Ye L, Jiang WG (2010) HuR, a key post-transcriptional regulator, and its implication in progression of breast cancer. Histol Histopathol 25: 1331–1340CASPubMedWeb of Science®Google Scholar Zhu S, Yoon K, Sterneck E, Johnson PF, Smart RC (2002) CCAAT/enhancer binding protein-beta is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling. Proc Natl Acad Sci USA 99: 207–212CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 30,Issue 18,September 14, 2011Canyon Dweller - “Antelope Canyon is a photographers‘ favourite for capturing reflected light from the walls of a slot canyon, but has now become very much a photographic cliché. I was thus delighted to find a new interpretation, viewing the canyon from the perspective of a praying mantis” says Ian Parker, a neurobiologist at the University of California Irvine. Ian Parker is an avid wilderness photographer and “the only Fellow of the Royal Society to have completed the world's toughest footrace!” Visit his homepage at http://parkerlab.bio.uci.edu Volume 30Issue 1814 September 2011In this issue FiguresReferencesRelatedDetailsLoading ...
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