No abstract

Although a number of target genes for the tumor suppressor p53 have been described, the mechanism of p53-dependent apoptosis is incompletely understood. Thus, it is essential to identify and characterize additional target genes that could mediate apoptosis. In the study reported here, we isolated a p53-regulated gene named NDRG1 (N-Myc down-regulated gene 1). Its expression is induced by DNA damage in a p53-dependent fashion. The promoter region of the NDRG1 gene contains a p53 binding site that confers p53-dependent transcriptional activation via a heterologous reporter. RNA interference and inducible gene expression approaches suggest that NDRG1 is necessary but not sufficient for p53-mediated caspase activation and apoptosis. This report further supports the notion that p53 controls a network of genes that are required for its apoptotic function.

Migration through 3D constrictions can cause nuclear rupture and mislocalization of nuclear proteins, but damage to DNA remains uncertain, as does any effect on cell cycle. Here, myosin II inhibition rescues rupture and partially rescues the DNA damage marker γH2AX, but an apparent block in cell cycle appears unaffected. Co-overexpression of multiple DNA repair factors or antioxidant inhibition of break formation also exert partial effects, independently of rupture. Combined treatments completely rescue cell cycle suppression by DNA damage, revealing a sigmoidal dependence of cell cycle on excess DNA damage. Migration through custom-etched pores yields the same damage threshold, with ∼4-µm pores causing intermediate levels of both damage and cell cycle suppression. High curvature imposed rapidly by pores or probes or else by small micronuclei consistently associates nuclear rupture with dilution of stiff lamin-B filaments, loss of repair factors, and entry from cytoplasm of chromatin-binding cGAS (cyclic GMP-AMP synthase). The cell cycle block caused by constricted migration is nonetheless reversible, with a potential for DNA misrepair and genome variation.

Summary Interleukin 24 (IL‐24) is a new member of the IL‐10 family of cytokines and it signals through two heterodimeric receptors: IL‐20R1/IL‐20R2 and IL‐22R1/IL‐20R2. Upon binding to its receptors, IL‐24 induces rapid activation of Stat‐1 and Stat‐3 transcription factors, which appear to play a role in cell survival and proliferation. Under physiological conditions, the major sources of IL‐24 are the activated monocytes and T helper 2 cells, whereas the major IL‐24 target tissues, based on the receptor expression pattern, are non‐haematopoietic in origin, and include skin, lung and reproductive tissues. Structurally and functionally, IL‐24 is highly conserved across species. This review highlights our current knowledge of IL‐24 as a cytokine, with much less emphasis placed on the non‐receptor‐mediated functions (a subject of several reviews) focused on in much of the earlier literature on IL‐24. The potential roles of IL‐24 as part of a complex cytokine network in wound healing, psoriasis and cancer are discussed.