Retinoblastoma‐independent regulation of cell proliferation and senescence by the p53–p21 axis in lamin A /C‐depleted cells

Summary The expression of A-type lamin is downregulated in several can-cers, and lamin defects are the cause of several diseases includinga form of accelerated aging. We report that depletion of laminA⁄C expression in normal human cells leads to a dramatic downre-gulation of the Rb family of tumor suppressors and a defect in cellproliferation. Lamin A⁄C-depleted cells exhibited a flat morphol-ogy and accumulated markers of cellular senescence. This senes-cent phenotype was accompanied by engagement of the p53tumor suppressor and induction of the p53 target gene p21 andwas prevented by small hairpin RNAs against p53, p21, or by theoncoprotein Mdm2. The expression of E2F target genes, normallyrequired for cell cycle progression, was downregulated after lam-in A⁄C depletion but restored after the inactivation of p53. A simi-lar senescenceresponse was observed in myoblasts from a patientwith a lamin A mutation causing muscular dystrophy. We thusreveal a previously unnoticed mechanism of controlling cell cyclegenes expression, which depends on p53 but does not require theretinoblastoma family of tumor suppressors and that can be rele-vant to understand the pathogenesis of laminopathies and per-haps aging.Key words: E2F; lamin A; muscular dystrophy; p21; p53; senes-cence.