Biomedical subjects

Fatima Mechta-Grigoriou

Publications and source records attributed to Fatima Mechta-Grigoriou.

4 recordsLinked to original sources

PubMed2003

c-jun regulation and function in the developing hindbrain.

Hindbrain development is a well-characterised segmentation process in vertebrates. The bZip transcription factor MafB/kreisler is specifically expressed in rhombomeres (r) 5 and 6 of the developing vertebrate hindbrain and is required for proper caudal hindbrain segmentation. Here, we provide evidence that the mouse protooncogene c-jun, which encodes a member of the bZip family, is coexpressed with MafB in prospective r5 and r6. Analysis of mouse mutants suggests that c-jun expression in these territories is dependent on MafB but independent of the zinc-finger transcription factor Krox20, another essential determinant of r5 development. Loss- and gain-of-function studies, performed in mouse and chick embryos, respectively, demonstrate that c-Jun participates, together with MafB and Krox20, in the transcriptional activation of the Hoxb3 gene in r5. The action of c-Jun is likely to be direct, since c-Jun homodimers and c-Jun/MafB heterodimers can bind to essential regulatory elements within the transcriptional enhancer responsible for Hoxb3 expression in r5. These data indicate that c-Jun acts both as a downstream effector and a cofactor of MafB and belongs to the complex network of factors governing hindbrain patterning.

Animals↗

PubMed2003

Novel activities of Mafb underlie its dual role in hindbrain segmentation and regional specification.

The bZip transcription factor Mafb is expressed in two segments of the developing vertebrate hindbrain: the rhombomeres 5 and 6. Loss of Mafb expression in the mouse mutant kreisler leads to elimination of r5 and to alterations of r6 regional identity. Here, we further investigated the role of Mafb in hindbrain patterning using gain-of-function experiments in the chick embryo. Our work has revealed novel functions for Mafb, including a positive autoregulatory activity, the capacity to repress Hoxb1 expression, and the capacity to synergise with or antagonise Krox20 activity. These different activities appear to be spatially restricted in the hindbrain, presumably due to interactions with other factors. Reinvestigation of the kreisler mutation indicated that it also results in an ectopic activation of Mafb in rhombomere 3, accounting for the previously described molecular alterations of this rhombomere in the mutant. Together, these data allow us to refine our view of the dual function of Mafb in both segmentation and specification of anteroposterior identity in the hindbrain.

Animals↗

PubMed2003

Impaired intervertebral disc formation in the absence of Jun.

Jun is a major component of the heterodimeric transcription factor AP-1 and is essential for embryonic development, as foetuses that lack Jun die at mid-gestation. Ubiquitous mosaic inactivation of a conditional Jun allele by cre/LoxP-mediated recombination was used to screen for novel functions of Jun and revealed that its absence results in severe malformations of the axial skeleton. More-specific Jun deletion by collagen2a1-cre demonstrated the essential function of Jun in the notochord and sclerotome. Mutant notochordal cells showed increased apoptosis, resulting in hypocellularity of the intervertebral discs. Subsequently, fusion of vertebral bodies caused a scoliosis of the axial skeleton. Thus, Jun is required for axial skeletogenesis by regulating notochord survival and intervertebral disc formation.

Animals↗

PubMed2002

Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-kappa B.

AP-1 family transcription factors have been implicated in the control of proliferation, apoptosis and malignant transformation. However, their role in oncogenesis is unclear and no recurrent alterations of AP-1 activities have been described in human cancers. Here, we show that constitutively activated AP-1 with robust c-Jun and JunB overexpression is found in all tumor cells of patients with classical Hodgkin's disease. A similar AP-1 activation is present in anaplastic large cell lymphoma (ALCL), but is absent in other lymphoma types. Whereas c-Jun is up-regulated by an autoregulatory process, JunB is under control of NF-kappa B. Activated AP-1 supports proliferation of Hodgkin cells, while it suppresses apoptosis of ALCL cells. Furthermore, AP-1 cooperates with NF-kappa B and stimulates expression of the cell-cycle regulator cyclin D2, proto-oncogene c-met and the lymphocyte homing receptor CCR7, which are all strongly expressed in primary HRS cells. Together, these data suggest an important role of AP-1 in lymphoma pathogenesis.

Cell Division↗