PubMed · 13532166
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P MILLIEZ, P SAMARCQ, S HARFOUCHE. 1957. [Acute glomerulonephritis].. https://pubmed.ncbi.nlm.nih.gov/13532166/
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Previous studies have demonstrated increased expression and phosphorylation of tyrosine kinase receptor (TrkA, TrkB) in lumbosacral DRG after chronic (6 weeks) spinal cord (T8-T10) injury. This study examined the effects of acute SCI (48 hours, 2 weeks) on TrkA and TrkB expression and phosphorylation, and CREB and c-Jun expression in DRG. A significant increase in the number of TrkA- (1.5-3-fold; P < or = 0.05), TrkB- (1.3-2.0-fold; P < or = 0.05), and phosphorylated Trk (pTrk)-immunoreactive (1.5-3-fold; P < or = 0.05) cells was observed in the L1, L6, and S1 DRG 48 hours, 2, or 6 weeks after SCI. A significant increase in the number of phosphorylated (p-) CREB-immunoreactive cells was observed in the L1, L2, L6, and S1 DRG 48 hours, 2, or 6 weeks after SCI. The largest changes in p-CREB-immunoreactivity were in L1 and L2 DRG (10-fold; P <or= 0.01) at 48 hours after SCI; however, changes were modest in bladder afferent neurons. After SCI, the overall number of c-Jun-immunoreactive cells in L1, L2, and S1 DRG was dramatically increased (3-10-fold; P < or = 0.01); however, only a low percentage of bladder afferent cells expressed c-Jun-IR before or after SCI. In summary, these results suggest that TrkA or TrkB may be involved in reorganization of micturition pathways after SCI. However, CREB or c-Jun may not be downstream transcription factors in Trk-mediated signaling cascades in micturition reflex pathways after SCI but may play a role in other, nonbladder SCI-induced changes.
The t(8;21)(q22;q22) translocation, present in 10-15% of acute myeloid leukemia (AML) cases results in the production of the AML1/ETO fusion protein. Expression of AML1/ETO in patients or mouse models is not sufficient to induce AML. Despite convincing evidence that AML1/ETO is directly involved in the pathogenesis of AML, the underlying mechanism is not well understood. Genetic and biochemical experiments suggest that AML1/ETO is a dominant inhibitor of the core binding factor (CBF) transcription complex that includes AML1 (RUNX1), the N-terminal fusion partner in the t(8;21). We generated and recently characterized a novel strain of transgenic mice in which the AML1/ETO cDNA was inserted into the Ly-6A gene that encodes Sca1, a well-characterized marker of murine hematopoietic stem cells. Unexpectedly, transgene expression assessed by flow cytometry was significantly lower than predicted in lymphocytes from these mice. We have confirmed this finding at the mRNA level and suggest that this phenotype is a consequence of dominant inhibition of transgene expression by AML1/ETO. The dominant negative characteristics of AML1/ETO may be important for AML pathogenesis and may provide a molecular target for therapeutic intervention.
Leukemic cells are defined by two main biological features: arrest of differentiation at a specific stage compatible with continued proliferation, and enhanced resistance to stress. Recent work shows that the leukemia-associated fusion protein PML-RAR can mediate both biological effects targeting independent pathways, through a unifying mechanism. Differentiation block is achieved through transcriptional silencing of genes physiologically regulated by RAR, which are involved in hematopoietic differentiation. In contrast, enhanced resistance to stress is due to the capacity of the fusion protein to cause degradation of the tumor suppressor p53, thus explaining the puzzling observation that mutations of p53 are remarkably rare in acute myeloid leukemias (AMLs). Interestingly, this latter phenomenon depends on expression of wild-type PML, acting as a molecular bridge between p53 and the fusion protein. Strikingly, both effects require a unifying molecular mechanism: aberrant recruitment of histone deacetylases (HDACs). Therefore, the study of this form of leukemia appears also of interest for a better understanding of the action of HDAC inhibitors, potential antitumor drugs that are at the early stages of clinical studies.