Dataset Information

Nuclear Envelope Rupture Is Enhanced by Loss of p53 or Rb.

ABSTRACT: The mammalian nuclear envelope (NE) forms a stable physical barrier between the nucleus and the cytoplasm, normally breaking down only during mitosis. However, spontaneous transient NE rupture in interphase can occur when NE integrity is compromised, such as when the nucleus experiences mechanical stress. For instance, deficiencies in the nuclear lamins and their associated proteins can cause NE rupture that is promoted by forces exerted by actin filaments. NE rupture can allow cytoplasmic nucleases to access chromatin, potentially compromising genome integrity. Importantly, spontaneous NE rupture was noted in several human cancer cell lines, but the cause of this defect is not known. Here, we investigated the mechanistic contributions of two major tumor suppressors, p53 (TP53) and Rb (RB1), to the repression of NE rupture. NE rupture was induced in normal human epithelial RPE-1 cells upon impairment of either Rb or p53 achieved by shRNA knockdown and CRISPR/Cas9 gene editing. NE rupture did not involve diminished expression of NE components or greater cell motility. However, cells that underwent NE rupture displayed a larger nuclear projection area. In conclusion, the data indicate that NE rupture in cancer cells is likely due to loss of either the Rb or the p53 pathway.Implications: These findings imply that tumor suppression by Rb and p53 includes the ability to prevent NE rupture, thereby protecting against genome alterations. Mol Cancer Res; 15(11); 1579-86. ©2017 AACR.

SUBMITTER: Yang Z

PROVIDER: S-EPMC5668176 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Nuclear Envelope Rupture Is Enhanced by Loss of p53 or Rb.

Yang Zhe Z Maciejowski John J de Lange Titia T

Molecular cancer research : MCR 20170815 11

The mammalian nuclear envelope (NE) forms a stable physical barrier between the nucleus and the cytoplasm, normally breaking down only during mitosis. However, spontaneous transient NE rupture in interphase can occur when NE integrity is compromised, such as when the nucleus experiences mechanical stress. For instance, deficiencies in the nuclear lamins and their associated proteins can cause NE rupture that is promoted by forces exerted by actin filaments. NE rupture can allow cytoplasmic nucle ...[more]

PMID: 28811362

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Project description:Recent in vitro and in vivo studies have highlighted the importance of the cell nucleus in governing migration through confined environments. Microfluidic devices that mimic the narrow interstitial spaces of tissues have emerged as important tools to study cellular dynamics during confined migration, including the consequences of nuclear deformation and nuclear envelope rupture. However, while image acquisition can be automated on motorized microscopes, the analysis of the corresponding time-lapse sequences for nuclear transit through the pores and events such as nuclear envelope rupture currently requires manual analysis. In addition to being highly time-consuming, such manual analysis is susceptible to person-to-person variability. Studies that compare large numbers of cell types and conditions therefore require automated image analysis to achieve sufficiently high throughput. Here, we present an automated image analysis program to register microfluidic constrictions and perform image segmentation to detect individual cell nuclei. The MATLAB program tracks nuclear migration over time and records constriction-transit events, transit times, transit success rates, and nuclear envelope rupture. Such automation reduces the time required to analyze migration experiments from weeks to hours, and removes the variability that arises from different human analysts. Comparison with manual analysis confirmed that both constriction transit and nuclear envelope rupture were detected correctly and reliably, and the automated analysis results closely matched a manual analysis gold standard. Applying the program to specific biological examples, we demonstrate its ability to detect differences in nuclear transit time between cells with different levels of the nuclear envelope proteins lamin A/C, which govern nuclear deformability, and to detect an increase in nuclear envelope rupture duration in cells in which CHMP7, a protein involved in nuclear envelope repair, had been depleted. The program thus presents a versatile tool for the study of confined migration and its effect on the cell nucleus.

Dataset Information

Nuclear Envelope Rupture Is Enhanced by Loss of p53 or Rb.

Publications

Nuclear Envelope Rupture Is Enhanced by Loss of p53 or Rb.

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