Suppression of proliferative defects associated with processing-defective lamin A mutants by hTERT or inactivation of p53.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, debilitating disease with early mortality and rapid onset of aging-associated pathologies. It is linked to mutations in LMNA, which encodes A-type nuclear lamins. The most frequent HGPS-associated LMNA mutation results in a protein, termed progerin, with an internal 50 amino acid deletion and, unlike normal A-type lamins, stable farnesylation. The cellular consequences of progerin expression underlying the HGPS phenotype remain poorly understood. Here, we stably expressed lamin A mutants, including progerin, in otherwise identical primary human fibroblasts to compare the effects of different mutants on nuclear morphology and cell proliferation. We find that expression of progerin leads to inhibition of proliferation in a high percentage of cells and slightly premature senescence in the population. Expression of a stably farnesylated mutant of lamin A phenocopied the immediate proliferative defects but did not result in premature senescence. Either p53 inhibition or, more surprisingly, expression of the catalytic subunit of telomerase (hTERT) suppressed the early proliferative defects associated with progerin expression. These findings lead us to propose that progerin may interfere with telomere structure or metabolism in a manner suppressible by increased telomerase levels and possibly link mechanisms leading to progeroid phenotypes to those of cell immortalization.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Brian A
BA
Kudlow
Monique N
MN
Stanfel
Christopher R
CR
Burtner
Elijah D
ED
Johnston
Brian K
BK
Kennedy
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D011371:Progeria / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D017368:Protein Prenylation; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C118860:E6 protein, Human papillomavirus type 6; D034904:Lamin Type A; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D011498:Protein Precursors; D016159:Tumor Suppressor Protein p53; C440308:lamin C; C090764:prelamin A; D019098:Telomerase