Lamin B receptor plays a key role in cellular senescence induced by inhibition of the proteasome

Abstract

Cellular senescence is a terminal growth arrest phenomenon in mammalian cells. Coordinated regulation of protein synthesis and degradation is required to maintain protein homeostasis in cells; however, senescent cells exhibit decreased activity of the proteasome, a major cellular proteolytic machinery, with an accumulation of proteins. Indeed, we showed that MG132, a proteasome inhibitor, induced cellular senescence through an accumulation of proteins in human cells. We then investigated the mechanisms of cellular senescence induced by protein accumulation by treating cells with MG132. We found that lamin B receptor (LBR), a nuclear membrane protein that regulates heterochromatin organization, was mislocalized and down‐regulated in cells on treatment with MG132. Importantly, enforced expression of LBR suppressed cellular senescence induced by MG132. We also showed that LBR was involved in the regulation of chromatin organization in senescent cells, and that endoplasmic reticulum stress and autophagy were likely to be involved in the mislocalization and down‐regulation of LBR. These findings indicate that decreased LBR function was responsible for the induction of cellular senescence by MG132, and thus suggest that protein accumulation caused by inhibition of the proteasome induced cellular senescence probably through chromatin dysregulation in human cells.

Knockdown of Lamin B1 and the Corresponding Lamin B Receptor Leads to Changes in Heterochromatin State and Senescence Induction in Malignant Melanoma

“…Here, the LBR was shown to interact with H3 methylated at lysine 9 (H3K9) [ 52 , 53 ]. The LBR was also reported to be mislocalized and downregulated in senescence induced cervical cancer cells by the protease inhibitor MG132 and therefore might play a key role in cellular senescence [ 54 ]. In agreement with our data, LMNB1 is discussed as a potential biomarker for detecting senescent cells due to its loss in human and murine cells undergoing senescence after DNA damage, replicative exhaustion or oncogene expression [ 55 , 56 ].…”

Extracellular Vesicles in Infrapatellar Fat Pad from Osteoarthritis Patients Impair Cartilage Metabolism and Induce Senescence

“…LBR is an integral membrane protein embedded in the inner nuclear envelope with structural impact on nuclear shape and chromatin organization. [26,27] LBR is involved in cellular senescence process, and its expression is decreased in senescent cells. [45] Several studies have showed that miRNAs affect cartilage senescence by suppressing or initiating LBR expression, thus relieving or exacerbating diseases progression.…”

“…[23,25] Recently, numerous reports have indicated the role of chromatin proteins in cellular senescence, such as the nuclear envelope protein, lamin B receptor (LBR). [26] Research showed that LBR deficiency promoted excess thymidine-induced cellular senescence in cancer cells. [27] Upregulated expression of LBR suppressed cellular senescence triggered by proteasome inhibitor.…”

“…[ 27 ] Upregulated expression of LBR suppressed cellular senescence triggered by proteasome inhibitor. [ 26 ] Evidences were found that inflammatory stimuli, such as IL‐1β, can facilitate senescent changes by enhancing SASP expression in a manner dependent upon oxidative and nitrosative stresses in OA. [ 28 ] Intra‐articular injection of senescent chondrocytes damages the potential of the mesenchymal stem cells (MSCs) to regenerate cartilage, suggesting that chondrocytes senescence contributes to OA development and progression.…”

The key role of a basic domain of histone H2B N‐terminal tail in the action of 5‐bromodeoxyuridine to induce cellular senescence

“…Human wild-type and tailless histone H2B were amplified with the combinations of the following primers and cloned into the EcoRI site of pCMV-EGFP, which expresses inserted genes fused with GFP at their C termini from the human cytomegalovirus (CMV) promoter [52]. Forward primers for wild-type and tailless histone H2B were as follows: 5 0 -CCGAATTCGCCACCATGCCTGAA CCGGCAAAATC-3 0 ( h H2B), 5 0 -CCGAATTCGCCACCA TGGAGAG CTACTCCATCTACGTGTAC-3 0 ( h H2B DN ) and 5 0 -AAGAATTCGCCACCATGAAGAAGCGCAAGC GCAGCCGCAAAG-3 0 ( h HBR-H2B DN ); reverse primers of histone H2B were as follows: 5 0 -CCGAATTCGCTTGG AGCTGGTGTACTT-3 0 .…”