title: Nuclear lamins and progerin are dispensable for antioxidant Nrf2 response to arsenic and cadmium.
abstract: Lamins are important constituents of the nuclear inner membrane and provide a platform for transcription factors and chromatin. Progerin, a C-terminal truncated lamin A mutant, causes premature aging termed Hutchinson-Gilford Progeria Syndrome (HGPS). Oxidative stress appears to be involved in the pathogenesis of HGPS, although the mechanistic role of progerin remains elusive. Here we examined whether nuclear lamins are important for a cellular antioxidant mechanism, and whether progerin compromises it. We investigated the activation of nuclear factor-E2-related factor 2 (Nrf2) which regulates various antioxidant genes including heme oxygenase-1 (HMOX1), following exposure to sodium arsenite or cadmium chloride in lamin knockdown human cell lines and primary HGPS human fibroblasts. Knocking down lamin A/C, or B, or all nuclear lamins simultaneously in three human cell lines (HaCaT, SW480, and K562) did not impair arsenite- or cadmium-induced activation of Nrf2. Progerin-expressing human primary HGPS fibroblasts showed lower basal levels of HMOX1 and NQO1 expression; however, in response to arsenic stress both normal and HGPS primary fibroblasts showed Nrf2 nuclear accumulation along with upregulation and phosphorylation of p62/SQSTM1 at Ser351, downregulation of Keap1, and comparable expression of an array of downstream Nrf2-regulated antioxidant genes. We also observed new forms of cleaved lamin A, B1 and B2 induced by cadmium stress although their roles in the Nrf2 antioxidant system need further investigation. These results suggest that the nuclear lamins and progerin have marginal roles in the activation of the antioxidant Nrf2 response to arsenic and cadmium.
authors.affiliation: Department of Biological Sciences, North Carolina State University, Campus Box 7633, Raleigh, NC 27695-7633, United States.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Department of Biological Sciences, North Carolina State University, Campus Box 7633, Raleigh, NC 27695-7633, United States.
authors.forename: Rima
authors.initials: R
authors.lastname: Majumdar
authors.affiliation: Department of Biological Sciences, North Carolina State University, Campus Box 7633, Raleigh, NC 27695-7633, United States. Electronic address: ytsuji@ncsu.edu.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tsuji
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D001151:Arsenic / Q000633:toxicity*; D002104:Cadmium / Q000633:toxicity*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism; D034904:Lamin Type A / Q000378:metabolism*; D034882:Lamins / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011371:Progeria / Q000378:metabolism / Q000473:pathology; D000071456:Sequestosome-1 Protein / Q000378:metabolism
chemical_list: D000975:Antioxidants; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D034904:Lamin Type A; D034882:Lamins; D051267:NF-E2-Related Factor 2; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C090764:prelamin A; D002104:Cadmium; D051547:Heme Oxygenase-1; D001151:Arsenic
keywords: Arsenic; Cadmium; HGPS; Lamin; Nrf2; Progerin