Abstract
Lamina-associated polypeptide 2α (LAP2α) localizes throughout the nucleoplasm and interacts with the fraction of lamins A/C that is not associated with the peripheral nuclear lamina. The LAP2α-lamin A/C complex negatively affects cell proliferation. Lamins A/C are encoded by LMNA, a single heterozygous mutation of which causes Hutchinson-Gilford progeria syndrome (HGPS). This mutation generates the lamin A variant progerin, which we show here leads to loss of LAP2α and nucleoplasmic lamins A/C, impaired proliferation, and down-regulation of extracellular matrix components. Surprisingly, contrary to wild-type cells, ectopic expression of LAP2α in cells expressing progerin restores proliferation and extracellular matrix expression but not the levels of nucleoplasmic lamins A/C. We conclude that, in addition to its cell cycle-inhibiting function with lamins A/C, LAP2α can also regulate extracellular matrix components independently of lamins A/C, which may help explain the proliferation-promoting function of LAP2α in cells expressing progerin.
Highlights
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease most commonly caused by a heterozygous mutation (c.1824C > T and p.G608G) in exon 11 of LMNA, the gene encoding the A-type lamins A and C (De Sandre-Giovannoli et al 2003; Eriksson et al 2003)
As it has been suggested that nucleoplasmic A-type lamins together with lamina-associated polypeptide 2α (LAP2α) have an important role in the regulation of cell proliferation (Gesson et al 2014), which has been found impaired in progerin-expressing cells (Bridger and Kill 2004; Hernandez et al 2010), we set out to determine the role of LAP2α in the progression of the cellular HGPS phenotype
Previous studies have shown that total LAP2 as well as LAP2α levels are decreased in HGPS cells (Scaffidi and Misteli 2005, 2008; Cenni et al 2011; Zhang et al 2011), but it remained unclear whether this is causally linked to the progression of the cellular HGPS phenotype
Summary
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease most commonly caused by a heterozygous mutation (c.1824C > T and p.G608G) in exon 11 of LMNA, the gene encoding the A-type lamins A and C (De Sandre-Giovannoli et al 2003; Eriksson et al 2003). As it has been suggested that nucleoplasmic A-type lamins together with LAP2α have an important role in the regulation of cell proliferation (Gesson et al 2014), which has been found impaired in progerin-expressing cells (Bridger and Kill 2004; Hernandez et al 2010), we set out to determine the role of LAP2α in the progression of the cellular HGPS phenotype. We demonstrate in primary HGPS patient fibroblasts and human telomerase reverse transcriptase (hTERT) immortalized fibroblasts that progerin expression down-regulates LAP2α expression at the transcriptional and translational level, causes loss of nucleoplasmic lamin A/C, and leads to impaired cell proliferation. Our data suggest that LAP2α may rescue proliferation of progerin-expressing cells by modulating the ECM expression independently of the nucleoplasmic LAP2α–lamin A/C complex
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