p53 regulates expression of nuclear envelope components in cancer cells

Abstract

Nuclear organisation and architecture are essential for the maintenance of genomic integrity as well as for the epigenetic regulations and gene expression. Disruption of lamin B1, major structural and functional member of the nuclear lamina, is observed in human laminopathies and in sporadic cancers, and leads to chromosomal rearrangements and alterations of gene expression. The tumour suppressor p53 has been shown to direct specific transcriptional programmes by regulating lamin A/C, however its relationship with lamin B1 has remained elusive. Here, we show that loss of p53 correlates with increased expression of members belonging to the nuclear pore complex and nuclear lamina and directly regulates transcription of lamin B1. We show that the genomic loci of a fraction of p53-dependent genes physically interact with lamin B1 and Nup210. This observation provides a possible mechanistic explanation for the p53-depedent changes of chromatin accessibility, with the consequent influence of expression and rearrangement of these genomic sites in pancreatic cancer. Overall, these data suggest a potential functional and biochemical regulatory network connecting p53 and nuclear architecture.

Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin

“…In fact, a greater variability of the chromatin radial distribution in proventriculus nuclei of the Drosophila Lamin mutants in comparison to WT nuclei can be observed by comparing three experimental groups ([117]). Thus, a dramatic loss or dysfunction of lamins during aging or disease [48, 138, 61, 62, 63] may contribute to the increased disorder in gene expression due to greater variability of the global chromatin architecture predicted in this work.…”

“…At the same time, attractions between heterochromatic TADs emerged as the main force of compartmentalization, while LAD-NE interactions are crucial for controlling the global spatial morphology of the nucleus [54, 56, 53]. However, a number of questions remains unanswered, related to sensitivity of the general organization principles with respect to global loss of chromatin-lamina interactions, which may occur in disease or senescence [51, 60, 61, 62, 63]. Also, the strength of TAD-TAD interactions can naturally vary during life of organisms.…”

ZNF750: A Novel Prognostic Biomarker in Metastatic Prostate Cancer

“…However, those mutations are present in a region of the protein that does not contain biologically active domains. Therefore, whether those mutations affect protein stability or other aspects of protein function remains to be explored [ 58 , 59 , 60 ]. Another question that still needs to be addressed is which molecular mechanism underlies the loss of ZNF750 expression in cancer.…”

“…Although it has already been recognized that prostate cancer progression is dependent on the ability of p63 to control EMT, a process that occurs in different types of cancer and is regulated by multiple mechanisms (i.e., other members of the p53 family or redox regulators), in the last decade several genomic studies focused on the genomic landscape of primary prostate cancer in order to identify other alterations potentially involved in tumor progression [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ]. Large chromosomal rearrangements affecting either the most common tumor suppressor gene, including p53 and PTEN, or oncogene, including c-Myc, have been described [ 23 , 51 ].…”

Gene expression in organoids: an expanding horizon

“…As a major gene involved in tumorigenesis as well as in cancer progression, TP53 regulates distinct structures at the level of nuclear envelope [ 120 ], N6-methyladenosine methylation profile [ 121 ], reticulons [ 122 , 123 ] and distinct nodes of the tumorigenic network [ 124 – 128 ]. Accordingly, very recent advances on the p53 biology [ 129 – 131 ] indicated a significant role for p53 in DNA damage response and apoptotic cell death [ 132 , 133 ], ferroptosis [ 134 ], ribosome biogenesis [ 135 ] as well as ncRNA [ 136 – 139 ].…”