Upregulated expression of lamin B receptor increases cell proliferation and suppresses genomic instability: implications for cellular immortalization

Abstract

Mammalian somatic cells undergo terminal proliferation arrest after a limited number of cell divisions, a phenomenon termed cellular senescence. However, cells acquire the ability to proliferate infinitely (cellular immortalization) through multiple genetic alterations. Inactivation of tumor suppressor genes such as p53, RB and p16 is important for cellular immortalization, although additional molecular alterations are required for cellular immortalization to occur. Here, we aimed to gain insights into these molecular alterations. Given that cellular immortalization is the escape of cells from cellular senescence, genes that regulate cellular senescence are likely to be involved in cellular immortalization. Because senescent cells show altered heterochromatin organization, we investigated the implications of lamin A/C, lamin B1 and lamin B receptor (LBR), which regulate heterochromatin organization, in cellular immortalization. We employed human immortalized cell lines, KMST‐6 and SUSM‐1, and found that expression of LBR was upregulated upon cellular immortalization and downregulated upon cellular senescence. In addition, knockdown of LBR induced cellular senescence with altered chromatin configuration. Additionally, enforced expression of LBR increased cell proliferation likely through suppression of genome instability in human primary fibroblasts that expressed the simian virus 40 large T antigen (TAg), which inactivates p53 and RB. Furthermore, expression of TAg or knockdown of p53 led to upregulated LBR expression. These observations suggested that expression of LBR might be upregulated to suppress genome instability in TAg‐expressing cells, and, consequently, its upregulated expression assisted the proliferation of TAg‐expressing cells (i.e. p53/RB‐defective cells). Our findings suggest a crucial role for LBR in the process of cellular immortalization.

Living Beyond Restriction: LBR promotes cellular immortalization by suppressing genomic instability and senescence

“…Consistently, ectopic expression of LBR increases the replicative lifespan of human fibroblasts expressing the simian virus 40 large T antigen, which inactivates p53 and RB proteins. Yet, this is not the case in human primary fibroblasts [13]. These data, together with results from the KMST-6 and SUSM-1 cell lines, suggest that LBR functions primarily in the absence of p53 and RB.…”

“…Knockdown of LBR decreased the proliferation of KMST-6 and SUSM-1 cells with an increased expression of several SASP-related genes, suggesting induction of senescence. Interestingly, the knockdown of LMNB1 has a marginal effect on senescence in KMST-6 and SUSM-1 cells, suggesting a lamin B1-independent role of LBR in senescence regulation [13]. Consistently, ectopic expression of LBR increases the replicative lifespan of human fibroblasts expressing the simian virus 40 large T antigen, which inactivates p53 and RB proteins.…”

“…En et al employed two human immortalized cell lines (KMST-6 and SUSM-1) to examine changes in lamin A/C (LMNA), lamin B1 (LMNB1), and LBR expression during cellular immortalization. While the expression of LMNB1 and LBR increases at the transcriptional level upon cellular immortalization, their expression decreases upon stress-induced senescence in KMST-6 and SUSM-1 cells, suggesting a potential role in the regulation of senescence and cellular immortalization [13].…”

“…In this issue of The FEBS Journal, En et al [13] identified a unique role for LBR in promoting cellular proliferation and immortalization in p53-and RB-deficient cells by maintaining their genome integrity and suppressing senescence. En et al employed two human immortalized cell lines (KMST-6 and SUSM-1) to examine changes in lamin A/C (LMNA), lamin B1 (LMNB1), and LBR expression during cellular immortalization.…”

“…Based on these observations, En et al hypothesized that LBR may promote cell proliferation and suppress senescence by increasing genome stability and maintaining chromatin organization. Indeed, they found that ectopic expression of LBR reduces the generation of CCFs and keeps chromatin in a tighter state, as assessed by a DNase I sensitivity assay in p53 and RB-inactivated cells [13]. By contrast, depletion of LBR increases the expression of repetitive DNA elements, such as LINE-1, Alu, a-satellite, and satellite II, all of which should be in a repressed state under normal conditions and whose expression has previously been shown to activate the cytosolic DNA sensor cGAS-STING pathway to drive the SASP [1,9,10].…”