Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) gene encodes for p35, the main activator of Cyclin-dependent kinase 5 (CDK5). The active p35/CDK5 complex is involved in numerous aspects of brain development and function, and its deregulation is closely associated to Alzheimer’s disease (AD) onset and progression. We recently showed that miR-15/107 family can negatively regulate CDK5R1 expression modifying mRNA stability. Interestingly, miRNAs belonging to miR-15/107 family are downregulated in AD brain while CDK5R1 is upregulated. Long non-coding RNAs (lncRNAs) are emerging as master regulators of gene expression, including miRNAs, and their dysregulation has been implicated in the pathogenesis of AD. Here, we evaluated the existence of an additional layer of CDK5R1 expression regulation provided by lncRNAs. In particular, we focused on three lncRNAs potentially regulating CDK5R1 expression levels, based on existing data: NEAT1, HOTAIR, and MALAT1. We demonstrated that NEAT1 and HOTAIR negatively regulate CDK5R1 mRNA levels, while MALAT1 has a positive effect. We also showed that all three lncRNAs positively control miR-15/107 family of miRNAs. Moreover, we evaluated the expression of NEAT1, HOTAIR, and MALAT1 in AD and control brain tissues. Interestingly, NEAT1 displayed increased expression levels in temporal cortex and hippocampus of AD patients. Interestingly, we observed a strong positive correlation between CDK5R1 and NEAT1 expression levels in brain tissues, suggesting a possible neuroprotective role of NEAT1 in AD to compensate for increased CDK5R1 levels. Overall, our work provides evidence of another level of CDK5R1 expression regulation mediated by lncRNAs and points to NEAT1 as a biomarker, as well as a potential pharmacological target for AD therapy.
Histone deacetylase 8 (HDAC8), a class I HDAC that modifies non-histone proteins such as p53, is highly expressed in different hematological neoplasms including a subtype of acute myeloid leukemia (AML) bearing inversion of chromosome 16 [inv(16)]. To investigate HDAC8 contribution to hematopoietic stem cell maintenance and myeloid leukemic transformation, we generated a zebrafish model with Hdac8 overexpression and observed an increase in hematopoietic stem/progenitor cells, a phenotype that could be reverted using a specific HDAC8 inhibitor, PCI-34051 (PCI). In addition, we demonstrated that AML cell lines respond differently to PCI treatment: HDAC8 inhibition elicits cytotoxic effect with cell cycle arrest followed by apoptosis in THP-1 cells, and cytostatic effect in HL60 cells that lack p53. A combination of cytarabine, a standard anti-AML chemotherapeutic, with PCI resulted in a synergistic effect in all the cell lines tested. We, then, searched for a mechanism behind cell cycle arrest caused by HDAC8 inhibition in the absence of functional p53 and demonstrated an involvement of the canonical WNT signaling in zebrafish and in cell lines. Together, we provide the evidence for the role of HDAC8 in hematopoietic stem cell differentiation in zebrafish and AML cell lines, suggesting HDAC8 inhibition as a therapeutic target in hematological malignancies. Accordingly, we demonstrated the utility of a highly specific HDAC8 inhibition as a therapeutic strategy in combination with standard chemotherapy.
Cornelia de Lange Syndrome (CdLS), which is reported to affect about 1 in 10,000 to 30,000 newborns, is a multisystem organ developmental disorder with relatively mild to severe effects. Among others, intellectual disability represents an important feature of this condition.Cornelia de Lange syndrome can result from mutations in at least five genes: NIPBL (nipped-B-like protein), SMC1A (structural maintenance of chromosomes 1A), SMC3 (structural maintenance of chromosomes 3), RAD21 (RAD21 Cohesin Complex Component), and HDAC8 (Histone deacetylase 8). It is believed that mutations in these genes cause CdLS by impairing the function of the cohesin complex (to which all the aforementioned genes contribute to the structure or function), disrupting gene regulation during critical stages of early development.Since intellectual disorder might result from alterations in neural development, in this work, we studied the role of Hdac8 gene in mouse neural stem cells and in vertebrate (D.rerio) brain development by knock-down and chemical inhibition experiments. An underlying features of Hdac8 deficiency is an increased cell death in the developing neural tissues, either in mouse NSCs and in zebrafish embryos.
The non critical string (2D gravity coupled to the matter with central charge D) is quantized taking care of both diffeomorphism and Weyl symmetries. In incorporating the gauge fixing with respect to the Weyl symmetry, through the condition R g = const, one modifies the classical result of Distler and Kawai. In particular one obtains the real string tension for an arbitrary value of central charge
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