Latifa Bakiri

Centro Nacional de Investigaciones Oncológicas, Madrid, Madrid, Spain

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Publications (45)455.86 Total impact

  • Latifa Bakiri, Erwin F. Wagner
    01/2015; DOI:10.4161/23723556.2014.990307
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    ABSTRACT: Altered epidermal differentiation characterizes numerous skin diseases affecting over 25% of the human population. Here we have identified Fra-2/AP-1 as a key regulator of terminal epidermal differentiation. Epithelial-restricted, ectopic expression of Fra-2 induced expression of epidermal differentiation genes, located within the Epidermal Differentiation Complex (EDC). Moreover, in a papilloma-prone background, reduced tumor burden was observed due to precocious keratinocyte differentiation by Fra-2 expression. Importantly, loss of Fra-2 in suprabasal keratinocytes is sufficient to cause skin barrier defects due to reduced expression of differentiation genes. Mechanistically, Fra-2 binds and transcriptionally regulates EDC gene promoters, which are co-occupied by the transcriptional repressor Ezh2. Fra-2 is methylated by Ezh2 on lysine residue 104 and remains transcriptionally inactive in non-differentiated keratinocytes. Upon keratinocyte differentiation, Fra-2 is C-terminally phosphorylated on serine 320 and threonione 322 by ERK1/2, leading to transcriptional activation. Thus, the induction of epidermal differentiation by Fra-2 is controlled by a dual mechanism involving Ezh2-dependent methylation and activation by ERK1/2-dependent phosphorylation.
    Genes & Development 01/2015; 29(2). DOI:10.1101/gad.249748.114 · 12.64 Impact Factor
  • Özge Uluçkan, Latifa Bakiri, Erwin F Wagner
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    ABSTRACT: Osteosarcoma (OS) is the most common primary tumor of bone with a high incidence in children. Treatment options for OS are limited, and once metastasized, the prognosis is very poor.Genetically engineered mouse models (GEMMs) are valuable tools to understand the mechanisms of tumorigenesis and to test possible therapies. In this chapter, we summarize the methods related to the isolation, characterization, and transplantation of OS cells obtained from GEMMs.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1267:297-305. DOI:10.1007/978-1-4939-2297-0_14 · 1.29 Impact Factor
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    ABSTRACT: Prostate cancer is a frequent cause of male death in the Western world. Relatively few genetic alterations have been identified, likely owing to disease heterogeneity. Here, we show that the transcription factor JUNB/AP-1 limits prostate cancer progression. JUNB expression is increased in low-grade prostate cancer compared with normal human prostate, but downregulated in high-grade samples and further decreased in all metastatic samples. To model the hypothesis that this downregulation is functionally significant, we genetically inactivated Junb in the prostate epithelium of mice. When combined with Pten (phosphatase and tensin homologue) loss, double-mutant mice were prone to invasive cancer development. Importantly, invasive tumours also developed when Junb and Pten were inactivated in a small cell population of the adult anterior prostate by topical Cre recombinase delivery. The resulting tumours displayed strong histological similarity with human prostate cancer. Loss of JunB expression led to increased proliferation and decreased senescence, likely owing to decreased p16(Ink4a) and p21(CIP1) in epithelial cells. Furthermore, the tumour stroma was altered with increased osteopontin and S100 calcium-binding protein A8/9 expression, which correlated with poor prognoses in patients. These data demonstrate that JUNB/AP-1 cooperates with PTEN signalling as barriers to invasive prostate cancer, whose concomitant genetic or epigenetic suppression induce malignant progression.Cell Death and Differentiation advance online publication, 19 December 2014; doi:10.1038/cdd.2014.213.
    Cell Death and Differentiation 12/2014; 22(4). DOI:10.1038/cdd.2014.213 · 8.39 Impact Factor
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    ABSTRACT: Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/ nicotinamide adenine dinucleotide (NAD+ ) metabolism, thereby causing DNA damage at early stages of tumorigenesis. Restoring NAD+ pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD+ can be prophylactic or therapeutic in HCC
    Cancer Cell 11/2014; 26(6). DOI:10.1016/j.ccell.2014.10.002 · 23.89 Impact Factor
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    ABSTRACT: Epithelial-to-mesenchymal transition (EMT) is essential for embryonic morphogenesis and wound healing and critical for tumour cell invasion and dissemination. The AP-1 transcription factor Fra-1 has been implicated in tumorigenesis and in tumour-associated EMT in human breast cancer. We observed a significant inverse correlation between Fra-1 mRNA expression and distant-metastasis-free survival in a large cohort of breast cancer patients derived from multiple array data sets. This unique correlation among Fos genes prompted us to assess the evolutionary conservation between Fra-1 functions in EMT of human and mouse cells. Ectopic expression of Fra-1 in fully polarized, non-tumourigenic, mouse mammary epithelial EpH4 cells induced a mesenchymal phenotype, characterized by a loss of epithelial and gain of mesenchymal markers. Proliferation, motility and invasiveness were also increased in the resulting EpFra1 cells, and the cells were tumourigenic and efficiently colonized the lung upon transplantation. Molecular analyses revealed increased expression of Tgfβ1 and the EMT-inducing transcription factors Zeb1, Zeb2 and Slug. Mechanistically, Fra-1 binds to the tgfb1 and zeb2 promoters and to an evolutionarily conserved region in the first intron of zeb1. Furthermore, increased activity of a zeb2 promoter reporter was detected in EpFra1 cells and shown to depend on AP-1-binding sites. Inhibiting TGFβ signalling in EpFra1 cells moderately increased the expression of epithelial markers, whereas silencing of zeb1 or zeb2 restored the epithelial phenotype and decreased migration in vitro and tumorigenesis in vivo. Thus Fra-1 induces changes in the expression of genes encoding EMT-related transcription factors leading to the acquisition of mesenchymal, invasive and tumorigenic capacities by epithelial cells. This study defines a novel function of Fra-1/AP-1 in modulating tgfb1, zeb1 and zeb2 expression through direct binding to genomic regulatory regions, which establishes a basis for future in vivo genetic manipulations and preclinical studies using mouse models.Cell Death and Differentiation advance online publication, 10 October 2014; doi:10.1038/cdd.2014.157.
    Cell Death and Differentiation 10/2014; 22(2). DOI:10.1038/cdd.2014.157 · 8.39 Impact Factor
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    Cell cycle (Georgetown, Tex.) 03/2014; 13(8). DOI:10.4161/cc.28514 · 5.01 Impact Factor
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population in Western societies, yet the underlying molecular pathways remain poorly understood. Here, we identify the dimeric Activator Protein 1 as a regulator of NAFLD. Fos-related antigen 1 (Fra-1) and Fos-related antigen 2 (Fra-2) prevent dietary NAFLD by inhibiting prosteatotic PPARγ signaling. Moreover, established NAFLD and the associated liver damage can be efficiently reversed by hepatocyte-specific Fra-1 expression. In contrast, c-Fos promotes PPARγ expression, while c-Jun exerts opposing, dimer-dependent functions. Interestingly, JunD was found to be essential for PPARγ signaling and NAFLD development. This unique antagonistic regulation of PPARγ by distinct AP-1 dimers occurs at the transcriptional level and establishes AP-1 as a link between obesity, hepatic lipid metabolism, and NAFLD.
    Cell metabolism 01/2014; 19(1):84-95. DOI:10.1016/j.cmet.2013.11.018 · 16.75 Impact Factor
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    ABSTRACT: The Activator Protein 1 (AP-1) transcription factor subunit Fos-related antigen 1 (Fra-1) has been implicated in liver fibrosis. Here we used loss-of-function as well as switchable, cell type-specific, gain-of-function alleles for Fra-1 to investigate the relevance of Fra-1 expression in cholestatic liver injury and fibrosis. Our results indicate that Fra-1 is dispensable in three well-established, complementary models of liver fibrosis. However, broad Fra-1 expression in adult mice results in liver fibrosis, which is reversible, when ectopic Fra-1 is switched off. Interestingly, hepatocyte-specific Fra-1 expression is not sufficient to trigger the disease, although Fra-1 expression leads to dysregulation of fibrosis-associated genes. Both opn and cxcl9 are controlled by Fra-1 in gain-of-function and loss-of-function experiments. Importantly, Fra-1 attenuates liver damage in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine-feeding cholestatic liver injury model. Strikingly, manipulating Fra-1 expression affects genes involved in hepatic transport and detoxification, in particular glutathione S-transferases. Molecular analyses indicate that Fra-1 binds to the promoters of cxcl9 and gstp1 in vivo. Furthermore, loss of Fra-1 sensitizes, while hepatic Fra-1 expression protects from acetaminophen-induced liver damage, a paradigm for glutathione-mediated acute liver failure. Conclusion: These data define a novel function of Fra-1/AP-1 in modulating the expression of detoxification genes and the adaptive response of the liver to bile acids/xenobiotic overload. (Hepatology 2014;58:261–273)
    Hepatology 01/2014; 59(1). DOI:10.1002/hep.26518 · 11.19 Impact Factor
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    ABSTRACT: Understanding the molecular pathogenesis of inflammatory liver disease is essential to design efficient therapeutic approaches. In hepatocytes, the dimeric transcription factor c-JUN/AP-1 is a major mediator of cell survival during hepatitis, although functions for other JUN proteins in liver disease are less defined. Here, we found that JUNB was specifically expressed in human and murine immune cells during acute liver injury. We analyzed the molecular function of JUNB in experimental models of hepatitis, including administration of concanavalin A (ConA) or α-galactosyl-ceramide, which induce liver inflammation and injury. Mice specifically lacking JUNB in hepatocytes displayed a mild increase in ConA-induced liver damage. However, targeted deletion of Junb in immune cells and hepatocytes protected against hepatitis in experimental models that involved NK/NKT cells. The absence of JUNB in immune cells decreased IFN-γ expression and secretion from NK and NKT cells, leading to reduced STAT1 pathway activation. Systemic IFN-γ treatment or adenovirus-based IRF1 delivery to Junb-deficient mice restored hepatotoxicity, and we demonstrate that Ifng is a direct transcriptional target of JUNB. These findings demonstrate that JUNB/AP-1 promotes cell death during acute hepatitis by regulating IFN-γ production in NK and NKT cells and thus functionally antagonizes the hepatoprotective function of c-JUN/AP-1 in hepatocytes.
    The Journal of clinical investigation 11/2013; DOI:10.1172/JCI70405 · 13.77 Impact Factor
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    ABSTRACT: Recent studies have established that the skeleton functions as an endocrine organ affecting metabolism through the osteoblast-derived hormone osteocalcin (Ocn). However, it is not fully understood how many transcription factors expressed in osteoblasts regulate the endocrine function. Here we show that mice with osteoblast-specific deletion of Fra-2 (Fosl2) have low bone mass, but increased body weight. In contrast, transgenic expression of Fra-2 in osteoblasts leads to increased bone mass and decreased body weight accompanied by reduced serum glucose and insulin levels, improved glucose tolerance and insulin sensitivity. In addition, mice lacking Fra-2 have reduced levels of circulating Ocn, but high Adiponectin (Adipoq), while Fra-2 transgenic mice exhibit high Ocn and low Adipoq levels. Moreover, Adipoq is transcriptionally repressed by Fra-2 in osteoblasts, where it is found expressed. These results demonstrate that Fra-2 expression in osteoblasts represents a novel paradigm for a transcription factor controlling the endocrine function of the skeleton.
    Journal of Cell Science 09/2013; 126(23). DOI:10.1242/jcs.134510 · 5.33 Impact Factor
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    ABSTRACT: Skin squamous cell carcinomas (SCCs) are the second most prevalent skin cancers. Chronic skin inflammation has been associated with the development of SCCs, but the contribution of skin inflammation to SCC development remains largely unknown. In this study, we demonstrate that inducible expression of c-fos in the epidermis of adult mice is sufficient to promote inflammation-mediated epidermal hyperplasia, leading to the development of preneoplastic lesions. Interestingly, c-Fos transcriptionally controls mmp10 and s100a7a15 expression in keratinocytes, subsequently leading to CD4 T-cell recruitment to the skin, thereby promoting epidermal hyperplasia that is likely induced by CD4 T-cell-derived IL-22. Combining inducible c-fos expression in the epidermis with a single dose of the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) leads to the development of highly invasive SCCs, which are prevented by using the anti-inflammatory drug sulindac. Moreover, human SCCs display a correlation between c-FOS expression and elevated levels of MMP10 and S100A15 proteins as well as CD4 T-cell infiltration. Our studies demonstrate a bidirectional cross-talk between premalignant keratinocytes and infiltrating CD4 T cells in SCC development. Therefore, targeting inflammation along with the newly identified targets, such as MMP10 and S100A15, represents promising therapeutic strategies to treat SCCs.
    Genes & development 09/2013; DOI:10.1101/gad.223339.113 · 12.64 Impact Factor
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    ABSTRACT: Chronic viral hepatitis C is characterized by iron accumulation in the liver and hepcidin regulates iron absorption. Hepatitis C core+1/ARFP is a novel protein produced by a second functional open reading frame within the core gene. Here, using reporter assays and HCV bicistronic replicons, we show that similar to core, core+1/ARFP decreases hepcidin expression in hepatoma cells. The AP1 binding site of the human hepcidin promoter, shown here to be relevant to basal promoter activity and to the repression by core, is essential for the down-regulation by core+1/ARFP while the previously described C/EBP and STAT sites are not. Consistently, expression of the AP1 components c-jun and c-fos obliterated the repressive effect of core and core+1/ARFP. In conclusion, we provide evidence that core+1/ARFP down-regulates AP1-mediated transcription, providing new insights into the biological role of core+1/ARFP, as well as the transcriptional modulation of hepcidin, the main regulator of iron metabolism.
    Journal of General Virology 04/2013; DOI:10.1099/vir.0.050328-0 · 3.53 Impact Factor
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    R. Hamacher, L. Bakiri, E.F. Wagner
    Journal of Hepatology 04/2013; 58:S39. DOI:10.1016/S0168-8278(13)60090-2 · 10.40 Impact Factor
  • Annals of the Rheumatic Diseases 02/2013; 72(Suppl 1):A27-A27. DOI:10.1136/annrheumdis-2013-203217.9 · 9.27 Impact Factor
  • Latifa Bakiri, Erwin F Wagner
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    ABSTRACT: Hepatocellular carcinoma (HCC), the most common form of primary liver cancer is the third leading cause of cancer-related cell death in human and the fifth in women worldwide. The incidence of HCC is increasing despite progress in identifying risk factors, understanding disease etiology and developing anti-viral strategies. Therapeutic options are limited and survival after diagnosis is poor. Therefore, better preventive, diagnostic and therapeutic tools are urgently needed, in particular given the increased contribution from systemic metabolic disease to HCC incidence worldwide. In the last three decades, technological advances have facilitated the generation of genetically engineered mouse models (GEMMs) to mimic the alterations frequently observed in human cancers or to conduct intervention studies and assess the relevance of candidate gene networks in tumor establishment, progression and maintenance. Because these studies allow molecular and cellular manipulations impossible to perform in patients, GEMMs have improved our understanding of this complex disease and represent a source of great potential for mechanism-based therapy development. In this review, we provide an overview of the current state of HCC modeling in the mouse, highlighting successes, current challenges and future opportunities.
    Molecular oncology 02/2013; DOI:10.1016/j.molonc.2013.01.005 · 5.94 Impact Factor
  • E. F. Wagner, L. Bakiri, A. Bozec
    Bone 12/2012; 51(6):S14. DOI:10.1016/j.bone.2012.08.042 · 4.46 Impact Factor
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    ABSTRACT: Understanding stage-dependent oncogenic mechanisms is critical to develop not only targeted therapies, but also diagnostic markers and preventive strategies. The mechanisms acting during cancer initiation remain elusive, largely owing to a lack of suitable animal models and limited availability of human precancerous lesions. Here we show using genetic mouse models specific for liver cancer initiation, that survival of initiated cancer cells is controlled by c-Jun, independently of p53, through suppressing c-Fos-mediated apoptosis. Mechanistically, c-Fos induces SIRT6 transcription, which represses survivin by reducing histone H3K9 acetylation and NF-κB activation. Importantly, increasing the level of SIRT6 or targeting the anti-apoptotic activity of survivin at the initiation stage markedly impairs cancer development. Moreover, in human dysplastic liver nodules, but not in malignant tumours, a specific expression pattern with increased c-Jun-survivin and attenuated c-Fos-SIRT6 levels was identified. These results reveal a regulatory network connecting stress response and histone modification in liver tumour initiation, which could be targeted to prevent liver tumorigenesis.
    Nature Cell Biology 10/2012; DOI:10.1038/ncb2590 · 20.06 Impact Factor
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    ABSTRACT: Squamous cell carcinomas (SCCs) are heterogeneous and aggressive skin tumors for which innovative, targeted therapies are needed. Here, we identify a p53/TACE pathway that is negatively regulated by FOS and show that the FOS/p53/TACE axis suppresses SCC by inducing differentiation. We found that epidermal Fos deletion in mouse tumor models or pharmacological FOS/AP-1 inhibition in human SCC cell lines induced p53 expression. Epidermal cell differentiation and skin tumor suppression were caused by a p53-dependent transcriptional activation of the metalloprotease TACE/ADAM17 (TNF-α-converting enzyme), a previously unknown p53 target gene that was required for NOTCH1 activation. Although half of cutaneous human SCCs display p53-inactivating mutations, restoring p53/TACE activity in mouse and human skin SCCs induced tumor cell differentiation independently of the p53 status. We propose FOS/AP-1 inhibition or p53/TACE reactivating strategies as differentiation-inducing therapies for SCCs.
    The Journal of clinical investigation 07/2012; 122(8):2898-910. DOI:10.1172/JCI63103 · 13.77 Impact Factor
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    ABSTRACT: Destruction of insulin-producing pancreatic β-cells by local autoimmune inflammation is a hallmark of type 1 diabetes. Histochemical analysis of pancreases from non-obese diabetic mice indicated activation of the transcription factor JunB/AP-1 (activator protein-1) after autoimmune infiltration of the islets. In vitro studies demonstrated that the cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ induce JunB expression as a protective mechanism against apoptosis in both human and rodent β-cells. The gene network affected was studied by microarray analysis showing that JunB regulates nearly 20% of the cytokine-modified β-cell genes, including the transcription factor ATF3. Direct transcriptional induction of ATF3 by JunB is a key event for β-cell survival after TNF-α+IFN-γ treatment. Moreover, pharmacological upregulation of JunB/ATF3 via increased cAMP protected rodent primary β-cells and human islet cells against pro-inflammatory mediators. These results were confirmed in genetically modified islets derived from Ubi-JunB transgenic mice. Our findings identify ATF3 as a novel downstream target of JunB in the survival mechanism of β-cells under inflammatory stress.
    Oncogene 08/2011; 31(13):1723-32. DOI:10.1038/onc.2011.353 · 8.56 Impact Factor

Publication Stats

2k Citations
455.86 Total Impact Points


  • 2008–2015
    • Centro Nacional de Investigaciones Oncológicas
      • BBVA Foundation – CNIO Cancer Cell Biology Programme
      Madrid, Madrid, Spain
  • 2009
    • Spanish National Centre for Cardiovascular Research
      Madrid, Madrid, Spain
  • 2005–2008
    • Research Institute of Molecular Pathology
      Wien, Vienna, Austria
  • 2000–2007
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France
  • 1997–2001
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France