Schwannomas are peripheral nerve sheath tumors that often occur in the setting of an inherited tumor predisposition syndrome, including Neurofibromatosis Types 1 (NF1) and 2 (NF2), Familial Schwannomatosis (FS) and Carney Complex (CNC). Loss of the NF2 tumor suppressor (encoding NF2, or Merlin) is associated with upregulation of the Rac1 small GTPase, which is thought to play a key role in mediating tumor formation. In prior studies, we generated a mouse model of schwannomas by performing tissue-specific knockout of the CNC gene Prkar1a, which encodes the type 1A regulatory subunit of Protein Kinase A. These tumors exhibited down-regulation of Nf2 protein and an increase in activated Rac1. To assess the requirement for Rac1 in schwannoma formation, we generated a double knockout of Prkar1a and Rac1 in Schwann cells and monitored tumor formation. Loss of Rac1 reduced tumor formation by reducing proliferation and enhancing apoptosis. Surprisingly, the reduction of tumor formation was accompanied by re-expression of the Nf2 protein. Furthermore, activated Rac1 was able to downregulate Nf2 in vitro in a Pak-dependent manner. These in vivo data indicate that activation of Rac1 is responsible for suppression of Nf2 protein production; deficiency of Nf2 in Schwann cells leads to loss of cellular growth control and tumor formation.. Further, PKA activation through mutation in Prkar1a is sufficient to initiate Rac1 signaling, with subsequent reduction of Nf2 and schwannomagenesis. Although in vitro evidence has shown that loss of Nf2 activates Rac1, our data indicates that signaling between Nf2 and Rac1 occurs in a bidirectional fashion, and these interactions are modulated by PKA.
Recent advances in probing the electronic structure of SiC with electron-excited luminescence techniques reveal the presence of localized electronic states near its surfaces and interfaces. These localized states form not only as a result of interface chemical bonding but also due to the formation of new lattice polytypes. Such electronic features are sensitive to the conditions under which the SiC is processed, as well as the application of electrical or mechanical stress. These localized changes on a nanometre scale provide a new perspective to Schottky barrier formation, band alignment, and polytypism in SiC as well as its performance in electronic devices.
Vascular smooth muscle cell (SMC) state/phenotype transitions underlie neointimal hyperplasia (IH) predisposing to cardiovascular diseases. Bromodomain protein BRD4 is a histone acetylation reader and enhancer mark that co-activates transcription elongation. CCAAT enhancer binding protein delta (CEBPD) is a transcription factor typically studied in adipogenesis and immune cell differentiation. Here we investigated the association between BRD4 and CEBPD in SMC state transition.Chromatin immunoprecipitation sequencing (ChIPseq) showed enrichment of BRD4 and histone acetylation (H3K27ac) at Cebpd and enhancer in rat carotid arteries undergoing IH. In vitro, BRD4 silencing with siRNA reduced SMC expression of CEBPD. Bromodomain-1 but not bromodoamin-2 accounted for this BRD4 function. Endogenous BRD4 co-IP'ed with CEBPD; Cebpd promoter and enhancer DNA fragments co-IP'ed with CEBPD or endogenous BRD4 (ChIP-qPCR). These co-IPs were abolished by the BRD4 bromodomain blocker JQ1. TNFa upregulated both BRD4 and CEBPD. Silencing CEBPD averted TNFa-induced inflammatory SMC state transition (heightened IL-1b, IL6, and MCP-1 mRNA levels), so did JQ1. CEBPD overexpression increased PDGFRa preferentially over PDGFRb; so did TNFa, and JQ1 abolished TNFa's effect.Our data reveal a BRD4/CEBPD partnership that promotes CEBPD's own transcription and inflammatory SMC state transition, thus shedding new light on epigenetic reader and transcription factor cooperative actions in SMC pathobiology.
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