p53 induces senescence through Lamin A/C stabilization-mediated nuclear deformation

Abstract

p53-mediated cellular senescence has been intensively investigated, because it is important for tumor suppressive function. In addition, p16/INK4A is well known to be critical for cellular senescence. However, detailed molecular mechanism or relevance between p53 and p16-mediated senescence has not been demonstrated yet. Here we show that p53 induces p16 through Lamin A/C stabilization via direct interaction. Stabilized Lamin A/C promotes degradation of BMI-1 and MEL-18 (Polycomb repressor complex 1, PRC1), which sequesters p16 promotor. Increased p53 can reduce BMI-1/MEL-18 and induce p16 expression via Lamin A/C. Elimination of Lamin A/C can abolish p53-induced p16 expression and BMI-1/MEL-18 reduction. As Lamin A/C expression is increased during cell differentiation, this mechanism seems to be very useful for selective induction of senescence in non-stem cells. Our results suggest that Lamin A/C-p53 network is important for p16/INK4A-mediated cellular senescence.

High-throughput gene screen reveals modulators of nuclear shape

“…, 2017 ). Interestingly, another study has recently demonstrated that overexpression or activation of p53 induces nuclear deformation reminiscent of the irregular nuclear shapes found in HGPS cells and induces cellular senescence ( Yoon et al. , 2019 ).…”

Lamin B1 deficiency promotes malignancy and predicts poor prognosis in gastric cancer

“…In recent decades, lamin mechanical stability [13]. Nevertheless, recent studies suggest that they also play a vital role in crucial cellular processes, such as replication of DNA, tumorigenesis, progression of cell cycle, mitotic spindle formation, aging, differentiation of adult stem cell, and chromatin organization [10,[14][15][16]. Studies on the lamins family have long focused on type A lamins, but few have focused on type B lamins, especially lamin B1.…”

p53 Enhances Artemisia annua L. Polyphenols-Induced Cell Death Through Upregulation of p53-Dependent Targets and Cleavage of PARP1 and Lamin A/C in HCT116 Colorectal Cancer Cells

“…Moreover, wild-type p53 stabilizes lamin A/C via direct interaction, and the stabilized lamin A/C with p53 binding (increased expression of lamin A/C) was associated with nuclear deformation [10]. These findings also support that p53 plays an important role in chromatin condensation, nuclear shrinkage and deformity by facilitating degradation of nuclear lamins [38,39], and induction of nuclear deformity by stabilizing lamin A/C which should be removed [10]. Therefore, the restoration or enhancement of p53 gene could be a good strategy for the treatment of pKAL in cancer patients who are not eligible for the conventional therapies due to the patient's poor condition.…”

“…Proteolysis of Lamins is associated with collapsed nuclei and chromatin condensation in p53-dependent apoptosis [38]. Moreover, wild-type p53 stabilizes lamin A/C via direct interaction, and the stabilized lamin A/C with p53 binding (increased expression of lamin A/C) was associated with nuclear deformation [10]. These findings also support that p53 plays an important role in chromatin condensation, nuclear shrinkage and deformity by facilitating degradation of nuclear lamins [38,39], and induction of nuclear deformity by stabilizing lamin A/C which should be removed [10].…”

“…In Korea, the incidence of colorectal cancer is highest among elderly women [7]. The tumor suppressor p53, known as the "Guardian of genome", still appears to be one of the major therapeutic targets for cancer due to its strong anticancer ability to respond to various cellular stress such as high reactive oxygen species (ROS), DNA damage, genomic instability, and senescence [8][9][10]. Inactivation of 53 signaling is a common feature of human cancer.…”