The size and shape of the nucleus are tightly regulated, indicating the physiological significance of proper nuclear morphology, yet the mechanisms and functions of nuclear size and shape regulation remain poorly understood. Correlations between altered nuclear morphology and certain disease states have long been observed, most notably many cancers are diagnosed and staged based on graded increases in nuclear size. Here we review recent studies investigating the mechanisms regulating nuclear size and shape, how mitotic events influence nuclear morphology, and the role of nuclear size and shape in subnuclear chromatin organization and cancer progression.

Altered nuclear size is associated with many cancers, and determining whether cancer-associated changes in nuclear size contribute to carcinogenesis necessitates an understanding of mechanisms of nuclear size regulation. Although nuclear import rates generally positively correlate with nuclear size, NTF2 levels negatively affect nuclear size, despite the role of NTF2 (also known as NUTF2) in nuclear recycling of the import factor Ran. We show that binding of Ran to NTF2 is required for NTF2 to inhibit nuclear expansion and import of large cargo molecules in Xenopus laevis egg and embryo extracts, consistent with our observation that NTF2 reduces the diameter of the nuclear pore complex (NPC) in a Ranbinding-dependent manner. Furthermore, we demonstrate that ectopic NTF2 expression in Xenopus embryos and mammalian tissue culture cells alters nuclear size. Finally, we show that increases in nuclear size during melanoma progression correlate with reduced NTF2 expression, and increasing NTF2 levels in melanoma cells is sufficient to reduce nuclear size. These results show a conserved capacity for NTF2 to impact on nuclear size, and we propose that NTF2 might be a new cancer biomarker.

Oxidative stress is implicated in neuronal death in a variety of neurodegenerative diseases. In the present study, P19 neurons obtained by the differentiation procedure from mouse teratocarcinoma P19 cells were used to investigate the ability of quercetin, a plant-derived flavonoid, to prevent neuronal death induced by exposure to 150 μM or 1.5 mM hydrogen peroxide (H(2)O(2)) for 24 h. Quercetin treatment improved viability of P19 neurons exposed to both types of oxidative injury. During the modest oxidative stress, quercetin diminished generation of reactive oxygen species (ROS) and prevented H(2)O(2)-induced nuclear condensation, increase in caspase 3/7 activity and rise in poly(APD-ribose) polymerase expression. Expression of Bcl-2 family members Bax and Bcl-2 was not affected by quercetin treatment at both the transcriptional and translational levels. During the severe oxidative injury, quercetin prevented H(2)O(2)-induced rise in ROS accumulation and changes in plasma membrane integrity and nuclear morphology. The obtained results suggest that neuroprotective effects of quercetin are related to its antioxidative action and prevention of events associated with programmed cell death cascade. In the light of these findings, one might assume beneficial effects of quercetin for the prevention of oxidative stress-driven neuronal loss in human aging and age-related neurodegenerative diseases.

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The major obstacle of successful tumor treatment with carboplatin (CBP) is the development of drug resistance. In the present study, we found that following treatment with CBP the amount of platinum which enters the human laryngeal carcinoma (HEp2)-derived CBP-resistant (7T) cells is reduced relative to the parental HEp2. As a consequence, the formation of reactive oxidative species (ROS) is reduced, the induction of endoplasmic reticulum (ER) stress is diminished, the amount of inter- and intrastrand cross-links is lower, and the induction of apoptosis is depressed. In HEp2 cells, ROS scavenger tempol, inhibitor of ER stress salubrinal, as well as gene silencing of ER stress marker CCAAT/enhancer-binding protein (CHOP) increases their survival and renders them as resistant to CBP as 7T cell subline but did not influence the survival of 7T cells. Our results suggest that in HEp2 cells CBP-induced ROS is a stimulus for ER stress. To the contrary, despite the ability of CBP to induce formation of ROS and activate ER stress in 7T cells, the cell death mechanism in 7T cells is independent of ROS induction and activation of ER stress. The novel signaling pathway of CBP-driven toxicity that was found in the HEp2 cell line, i.e. increased ROS formation and induction of ER stress, may be predictive for therapeutic response of epithelial cancer cells to CBP-based therapy.