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Mitotic defects lead to pervasive aneuploidy and accompany loss of RB1 activity in mouse LmnaDhe dermal fibroblasts.

ABSTRACT: Lamin A (LMNA) is a component of the nuclear lamina and is mutated in several human diseases, including Emery-Dreifuss muscular dystrophy (EDMD; OMIM ID# 181350) and the premature aging syndrome Hutchinson-Gilford progeria syndrome (HGPS; OMIM ID# 176670). Cells from progeria patients exhibit cell cycle defects in both interphase and mitosis. Mouse models with loss of LMNA function have reduced Retinoblastoma protein (RB1) activity, leading to aberrant cell cycle control in interphase, but how mitosis is affected by LMNA is not well understood.We examined the cell cycle and structural phenotypes of cells from mice with the Lmna allele, Disheveled hair and ears (Lmna(Dhe)). We found that dermal fibroblasts from heterozygous Lmna(Dhe) (Lmna(Dhe/+)) mice exhibit many phenotypes of human laminopathy cells. These include severe perturbations to the nuclear shape and lamina, increased DNA damage, and slow growth rates due to mitotic delay. Interestingly, Lmna(Dhe/+) fibroblasts also had reduced levels of hypophosphorylated RB1 and the non-SMC condensin II-subunit D3 (NCAP-D3), a mitosis specific centromere condensin subunit that depends on RB1 activity. Mitotic check point control by mitotic arrest deficient-like 1 (MAD2L1) also was perturbed in Lmna(Dhe/+) cells. Lmna(Dhe/+) fibroblasts were consistently aneuploid and had higher levels of micronuclei and anaphase bridges than normal fibroblasts, consistent with chromosome segregation defects.These data indicate that RB1 may be a key regulator of cellular phenotype in laminopathy-related cells, and suggest that the effects of LMNA on RB1 include both interphase and mitotic cell cycle control.

SUBMITTER: Pratt CH

PROVIDER: S-EPMC3064591 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Mitotic defects lead to pervasive aneuploidy and accompany loss of RB1 activity in mouse LmnaDhe dermal fibroblasts.

Pratt C Herbert CH Curtain Michelle M Donahue Leah Rae LR Shopland Lindsay S LS

PloS one 20110325 3

<h4>Background</h4>Lamin A (LMNA) is a component of the nuclear lamina and is mutated in several human diseases, including Emery-Dreifuss muscular dystrophy (EDMD; OMIM ID# 181350) and the premature aging syndrome Hutchinson-Gilford progeria syndrome (HGPS; OMIM ID# 176670). Cells from progeria patients exhibit cell cycle defects in both interphase and mitosis. Mouse models with loss of LMNA function have reduced Retinoblastoma protein (RB1) activity, leading to aberrant cell cycle control in in ...[more]

PMID: 21464947

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Project description:Lumican is overexpressed in lung cancer cells and has been implicated in the pathogenesis of tumorigenesis and regulation of cancer cell invasion. Lumican is robustly associated with the binding of p120-catenin protein to modulate cell metastasis. However, its role in cancer cell proliferation is still unclear. This study investigated the effect of lumican on the cell division including mitosis and cytokinesis in non-small lung cancer cells. We found that the downregulation of lumican prolonged the doubling time of cells and retarded the cell growth in H460 and A549 cells. Along with tubulin, lumican localized to the mitotic spindle and centrosome during the metaphase-anaphase stage. The cell cycle was retained in the G2/M phase after the downregulation of lumican. Interestingly, lumican was found to play important roles in central spindle and midbody formation during cytokinesis. Lumican interacted with the midbody-associated proteins such as MKLP1, Aurora B, and ECT2. Notably, the downregulation of lumican decreased the level of MKLP1 accompanied by the retention of midbody-residual that resulted in multi-nucleated cells. Downregulation of lumican promoted the chromosome missegregation and the increment of the bi-/multinucleated cells. The results of this study indicated that lumican associated with tubulin is crucial for spindle fiber formation and midbody assembly in cell division. Downregulation of lumican displayed the defects in mitotic spindle assembly/dynamics and improper kinetochore-microtubules attachment that led to increase aneuploidy. This emerging property of lumican is suggested to tightly control chromosome segregation during cell division in lung cancer cells.Abbreviations: ESCRT: endosomal sorting complex required for transport; PRC1: protein regulator of cytokinesis 1; Nci: negative control siRNA; Lumi: lumican siRNAs; MKLP1: mitotic kinesin-like protein 1; H460LD and A549LD: H460 and A549 cell lines with less expressed lumican.

Dataset Information

Mitotic defects lead to pervasive aneuploidy and accompany loss of RB1 activity in mouse LmnaDhe dermal fibroblasts.

Publications

Mitotic defects lead to pervasive aneuploidy and accompany loss of RB1 activity in mouse LmnaDhe dermal fibroblasts.

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