NOL3 blocking peptide

Background: Right ventricular (RV) failure (RVF) is a vexing problem facing patients with various disease processes and carries a high mortality. RVF is a poorly understood phenomenon with limited treatment options. In mammalian fetal circulation, the right ventricle is the systemic ventricle. In neonates, however, the left ventricle assumes that role and gradually thickens compared with the right ventricle. This process, known as right ventricular involution (RVI), is poorly understood. We sought to define the time course and identify mechanisms involved in RVI. Methods: Wild-type mice were bred and sacrificed on day of life (DOL) 1, 4, 8, 16, and 30 to evaluate left ventricular (LV) and RV wall thickness and apoptosis. A terminal deoxynucleotidyl transferase nick-end labeling assay and RNA sequencing were performed to measure changes during RVI. Results: Morphometric analysis demonstrated the changes in RV and LV wall thickness occurring between DOL 1 and DOL 16 (RV: LV, 0.53: 0.44; P=.03). In addition, apoptosis was most active early, with the highest percentage of apoptotic cells on DOL 1 (1.0%) and a significant decrease by DOL 30 (0.23%) (P=.02). Similarly, expression of the proapoptotic genes BCL2l11 and Pawr were increased at DOL 1, and the antiapoptotic genes Nol3 and Naip2 were significantly increased at DOL 30. Conclusions: RVI is a misnomer, but significant changes occur early (by DOL 16) in neonatal mouse hearts. Apoptosis plays a role in RVI, but whether manipulation of apoptotic pathways can prevent or reverse RVI is unknown and warrants further investigation.

Inhibition of apoptosis is critical for carcinogenesis. ARC (apoptosis repressor with caspase recruitment domain) is an endogenous inhibitor of apoptosis that antagonizes both intrinsic and extrinsic apoptosis pathways. Although normally expressed in striated myocytes and neurons, ARC is markedly induced in a variety of primary human epithelial cancers and renders cancer cells resistant to killing. The mechanisms that mediate the induction of ARC in cancer are unknown. Herein we demonstrate that increases in ARC abundance are stimulated by Ras through effects on transcription and protein stability. Overexpression of activated N-Ras or H-Ras in normal cells is sufficient to increase ARC mRNA and protein levels. Similarly, transgenic expression of activated H-Ras induces ARC in both the normal mammary epithelium and resulting tumors of intact mice. Conversely, knockdown of endogenous N-Ras in breast and colon cancer cells significantly reduces ARC mRNA and protein levels. The promoter of the Nol3 locus, encoding ARC, is activated by N-Ras and H-Ras in a MEK/ERK-dependent manner. Ras also stabilizes ARC protein by suppressing its polyubiquitination and subsequent proteasomal degradation. In addition to the effects of Ras on ARC abundance, ARC mediates Ras-induced cell survival and cell cycle progression. Thus, Ras induces ARC in epithelial cancers, and ARC plays a role in the oncogenic actions of Ras.