Senescent Cells as Drivers of Age-Related Diseases
Shamim I. Ahmad in Aging: Exploring a Complex Phenomenon, 2017
The nuclear envelope is lined by the nuclear lamina, a dense fibrillary network which provides mechanical support and regulates size, shape, and stability of the nucleus [85,86]. Nuclear lamina also partakes in a number of other functions including regulation of DNA synthesis, RNA transcription, and chromatin organization [87]. In mammals, the lamina contains major structural proteins categorized as type A (lamin A and C) and type B (lamin B1 and B2) lamins based on their isoelectric points [85]. Nuclear lamins are dynamic structures that are assembled and disassembled throughout the cell cycle. Lamin A and C are derived from the gene LMNA by alternative splicing and are expressed by non-proliferating and differentiated cells. Lamin B1 and B2 are encoded by separate genes LMNB1 and LMNB2 respectively and are strongly expressed by dividing and undifferentiated cells [88–90]. While there are two types of lamin B, expression of one or the other is sufficient for cell survival [86,91]. Expression of type A and B lamins are differentially regulated in specific tissues during embryogenesis [91,92].
Manipulating the Intracellular Trafficking of Nucleic Acids
Kenneth L. Brigham in Gene Therapy for Diseases of the Lung, 2020
The nucleus is bounded by the nuclear envelope, which encloses chromatin and the machinery necessary for gene transcription. The nucleus is a dynamic structure, which disassembles at the onset of mitosis and reassembles during telophase. The envelope consists of two membrane bilayers, posing a considerable hydrophobic barrier to macromolecular transport (Fig. 3). The outer nuclear membrane is continuous with the endoplasmic reticulum, and with the inner nuclear membrane forms a perinuclear space that is continuous with the endoplasmic reticulum lumen (82,83). The inner nuclear membrane is supported internally by the nuclear lamina, a network of lamin proteins that lines the inner side of the envelope (82). The lamina also is thought to provide attachment sites for chromatin (84-86). The very interior of the nucleus is a network of DNA, RNA, and proteins. It is the active transcriptions sites that are the targets of gene delivery.
Mitochondrial Stress and Cellular Senescence
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
Lamin B1 is a protein which comprises part of the nuclear lamina and helps in maintaining proper nuclear structure and function (Camps, Erdos, and Ried 2015). Senescent cells induced through MiDAS have lower expression of lamin B1 relative to dividing and undifferentiated cells (Wiley et al. 2016). Lamin B1 loss is also observed in RS and OIS (Freund et al. 2012). Cells induced to senesce by DNA-damaging agents, such as UV and X-ray irradiation, also exhibit decline in lamin B1 (Freund et al. 2012; Wang et al. 2017). Loss of lamin B1 in senescent cells is linked to the formation of SAHF (Sadaie et al. 2013) and nuclear blebs (Shimi et al. 2011).
A review of protein-protein interaction and signaling pathway of Vimentin in cell regulation, morphology and cell differentiation in normal cells
Published in Journal of Receptors and Signal Transduction, 2022
Danial Hashemi Karoii, Hossein Azizi
The IFs that make up the nuclear lamina surrounding the inner nuclear membrane has been shown to influence gene transcription through protein-protein interactions and DNA replication [15,16]. On the other hand, Vimentin has been characterized as a possible transcriptional regulator since it can sequester transcriptional determinants and interact with them, such as p53 and menin, which collaborates with transcription factors AP1 and JunD [16,17]. Furthermore, Peter Traub and colleagues’ long-term research shows an altogether new aspect of Vimentin’s cellular and molecular activities. They have shown Vimentin’s capacity to interact with different specialized DNA structures, including, among other things, satellite DNA, telomere DNA retroposons, and mitochondrial DNA in a number of publications [18,19]. This connection between cytoplasmic Vimentin and genomic DNA is facilitated by VIF, which is found in nuclei and mitochondria. Wang and colleagues discovered that the N-terminal head of Vimentin is responsible for DNA binding. Recent studies have shown that Vimentin is related to mRNA for control stability, RNA binding, and double-stranded RNA binding [20–22].
Ambient PM2.5 exposure causes cellular senescence via DNA damage, micronuclei formation, and cGAS activation
Published in Nanotoxicology, 2022
Tao Wu, Shengmin Xu, Biao Chen, Lingzhi Bao, Jie Ma, Wei Han, An Xu, Kwan Ngok Yu, Lijun Wu, Shaopeng Chen
It was puzzling that although cGAS accumulated on most MNs, there was no cGAS accumulation on a tiny minority of MNs following PM2.5 exposures. Research from a previous study demonstrated that NE rupture in primary nuclei was associated with disorganization in the nuclear lamina of cells (Hatch et al. 2013). According to the previous finding, those MNs gathered cGAS might have defects in the nuclear lamina assembly. To detect the integrity of lamina, we labeled cGAS and lamin A/C in fibroblasts exposed to PM2.5, and found that although cGAS gathered in most MNs with the discontinuous nuclear rim of lamin A/C, indicating disruption of MNs, a few MNs with the continuous nuclear rim of lamin A/C still accumulated cGAS. Further labeling of lamin B1 showed that almost every MN with discontinuous nuclear rim of lamin B1 gathered cGAS. Co-staining of laminB1 and lamin A/C showed that MNs with continuous nuclear rim of lamin A/C presented discontinuous nuclear rim of lamin B1. Statistical results showed that both lamin B1 (about 90%) and lamin A/C (about 40%) had different degrees of rupture, and the rate of lamin B1 disorganization was closely related to the rate of cGAS gathering (about 80%). Consistent with the localization of lamina, the protein levels of lamin B1 decreased significantly and lamin A/C did not downregulate that much. Thus, we demonstrated that disrupted MNs were a source of cGAS activation to aggravate cellular senescence and lamin B1 triggered MNs disruption upon PM2.5 exposures.
Advances in autophagy as a target in the treatment of tumours
Published in Journal of Drug Targeting, 2022
Yingying Li, Shan Gao, Xiyou Du, Jianbo Ji, Yanwei Xi, Guangxi Zhai
If autophagy in normal tissues is inhibited, homeostasis will be destroyed, leading to DNA damage, reactive oxygen species (ROS) accumulation and inflammatory response, which can promote the occurrence of tumour. Therefore, autophagy can inhibit the occurrence of tumour to a certain extent. Beclin1, as an autophagy regulatory gene, is an essential molecule in the process of autophagy nuclear formation, and its low expression is considered as a marker of tumorigenesis. A research found that the expression level of Beclin1 in 80 cases of thyroid cancer tissues was at a low level, furthermore, interference with Beclin1 gene expression would induce the occurrence of leiomyoma, breast cancer, ovarian cancer, cervical cancer and liver cancer [12]. The specific molecular mechanism is that the low expression of Beclin1 could induce the activation of anti-apoptotic protein (Bcl-2), which could inhibit the apoptosis of normal cells, so that the cells have the characteristics of cancer and promote tumour occurrence. In addition, tumorigenesis may also be due to the imbalance between proto-oncogene and tumour suppressor gene. For example, nuclear lamina protein Lamin B1, as a substrate after carcinogenic injury, could interact with autophagy-related protein LC3 or gene ATG8, which could enhance cell ageing, reduce cell life span and inhibit oncogene activity, thus inhibiting the occurrence of cancer cells [15]. Therefore, selective nuclear lamina degradation by autophagy may play a vital role in restricting tumorigenesis and maintaining cell and tissue integrity.