Accumulation of multiple forms of lamin A with down‐regulation of FACE‐1 suppresses growth in senescent human cells

Ukekawa, Ryo; Miki, Kensuke; Fujii, Michihiko; Hirano, Hisashi; Ayusawa, Dai

doi:10.1111/j.1365-2443.2007.01057.x

Cited by 18 publications

(14 citation statements)

References 42 publications

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“…Previous studies have implied a role for either pre-lamin A accumulation or progerin in normal aging (McClintock et al, 2006;Ukekawa et al, 2007;Scaffidi & Misteli, 2008) and that these in concert with some other age-dependent mechanisms may be required for the observed adverse effects on nuclear morphology and cellular proliferation in aged cells (Kudlow & Kennedy, 2006). Our current findings suggest that oxidative damage to lamin A thiols has an important influence on cellular aging.…”

Section: Discussionsupporting

confidence: 59%

“…Abnormal nuclear shapes and low levels of progerin are present in fibroblasts and skin tissue of old individuals (McClintock et al, 2006, Scaffidi & Misteli, 2008. In addition, pre-lamin A accumulation has also been reported during cellular senescence (Ukekawa et al, 2007;Candelario et al, 2008, Huang et al, 2008. Interestingly, reports have also shown a decreased expression of lamin A in different cell types of old mice (Duque & Rivas, 2006).…”

Section: Introductionmentioning

confidence: 98%

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Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation

et al. 2011

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SummaryPre-lamin A and progerin have been implicated in normal aging, and the pathogenesis of age-related degenerative diseases is termed 'laminopathies'. Here, we show that mature lamin A has an essential role in cellular fitness and that oxidative damage to lamin A is involved in cellular senescence. Primary human dermal fibroblasts (HDFs) aged replicatively or by pro-oxidants acquire a range of dysmorphic nuclear shapes. We observed that conserved cysteine residues in the lamin A tail domain become hyperoxidized in senescent fibroblasts, which inhibits the formation of lamin A inter-and intramolecular disulfide bonds. Both in the absence of lamin A and in the presence of a lamin A cysteine-toalanine mutant, which eliminates these cysteine residues (522, 588, and 591), mild oxidative stress induced nuclear disorganization and led to premature senescence as a result of decreased tolerance to ROS stimulators. Human dermal fibroblasts lacking lamin A or expressing the lamin A cysteine-to-alanine mutant displayed a gene expression profile of ROS-responsive genes characteristic of chronic ROS stimulation. Our findings suggest that the conserved C-terminal cysteine residues are essential for lamin A function and that loss or oxidative damage to these cysteine residues promotes cellular senescence.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 98%

Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation

et al. 2011

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“…2E). Importantly, downregulation of ZMPSTE24 appears to be a feature of ageing cells (Ukekawa et al, 2007), including those from vascular smooth muscle Ragnauth et al, 2010). However, because ZMPSTE24 was not downregulated in OD fibroblasts, some effect on prelamin A farnesylation and/or stability appears to be more likely in those cells.…”

Section: Zmpste24 Is Downregulated In Cells From Centenariansmentioning

confidence: 94%

Centenarian lamins: rapamycin targets in longevity

Lattanzi

Ortolani

Columbaro

et al. 2013

Journal of Cell Science

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The dynamic organisation of the cell nucleus is profoundly modified during growth, development and senescence as a result of changes in chromatin arrangement and gene transcription. A plethora of data suggests that the nuclear lamina is a key player in chromatin dynamics and argues in favour of a major involvement of prelamin A in fundamental mechanisms regulating cellular senescence and organism ageing. As the best model to analyse the role of prelamin A in normal ageing, we used cells from centenarian subjects. We show that prelamin A is accumulated in fibroblasts from centenarians owing to downregulation of its specific endoprotease ZMPSTE24, whereas other nuclear envelope constituents are mostly unaffected and cells do not enter senescence. Accumulation of prelamin A in nuclei of cells from centenarians elicits loss of heterochromatin, as well as recruitment of the inactive form of 53BP1, associated with rapid response to oxidative stress. These effects, including the prelamin-A-mediated increase of nuclear 53BP1, can be reproduced by rapamycin treatment of cells from younger individuals. These data identify prelamin A and 53BP1 as new targets of rapamycin that are associated with human longevity. We propose that the reported mechanisms safeguard healthy ageing in humans through adaptation of the nuclear environment to stress stimuli.

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“…Recently, A-type lamins have been linked to the maintenance and regeneration of a number of mesenchymal tissues and have been proposed to be regulators of mesenchymal stem cell regeneration (Gotzmann & Foisner, 2006). Both lamin A and progerin have been implicated in physiological ageing (Duque & Rivas, 2006;McClintock et al 2006;Scaffidi & Misteli, 2006;Afilalo et al 2007;Cao et al 2007;Ukekawa et al 2007;Candelario et al 2008;Huang et al 2008). Tissues affected by lamin A/C mutations often show degenerative changes accompanied by increased fibrosis and/or lipid accumulation (Hutchison & Worman, 2004).…”

Section: A-type Lamins At the Crossroads Between Tissue Regeneration mentioning

confidence: 99%

Adult stem cell maintenance and tissue regeneration in the ageing context: the role for A‐type lamins as intrinsic modulators of ageing in adult stem cells and their niches

Pekovic

Hutchison

2008

Journal of Anatomy

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Adult stem cells have been identified in most mammalian tissues of the adult body and are known to support the continuous repair and regeneration of tissues. A generalized decline in tissue regenerative responses associated with age is believed to result from a depletion and/or a loss of function of adult stem cells, which itself may be a driving cause of many age-related disease pathologies. Here we review the striking similarities between tissue phenotypes seen in many degenerative conditions associated with old age and those reported in age-related nuclear envelope disorders caused by mutations in the LMNA gene. The concept is beginning to emerge that nuclear filament proteins, A-type lamins, may act as signalling receptors in the nucleus required for receiving and/ or transducing upstream cytosolic signals in a number of pathways central to adult stem cell maintenance as well as adaptive responses to stress. We propose that during ageing and in diseases caused by lamin A mutations, dysfunction of the A-type lamin stress-resistant signalling network in adult stem cells, their progenitors and/or stem cell niches leads to a loss of protection against growth-related stress. This in turn triggers an inappropriate activation or a complete failure of self-renewal pathways with the consequent initiation of stress-induced senescence. As such, A-type lamins should be regarded as intrinsic modulators of ageing within adult stem cells and their niches that are essential for survival to old age.

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Accumulation of multiple forms of lamin A with down‐regulation of FACE‐1 suppresses growth in senescent human cells

Cited by 18 publications

References 42 publications

Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation

Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation

Centenarian lamins: rapamycin targets in longevity

Adult stem cell maintenance and tissue regeneration in the ageing context: the role for A‐type lamins as intrinsic modulators of ageing in adult stem cells and their niches

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