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Excess lamins delay the cell cycle.

On page 83, Dorner et al. report that overexpression of a lamina-associated protein slows cell proliferation and promotes differentiation in vitro. The findings suggest that laminopathy symptoms may not be due to structural weakness in the tissue, but rather to a failure of stem cells to properly regenerate damaged or aging tissues.

A-type lamins are found at the nuclear periphery and in the nucleoplasm of differentiated cells and have been implicated in cell cycle regulation and chromatin function. An associated protein, LAP2, interacts with the hypophosphorylated form of Rb, which represses entry into S-phase by blocking activation of E2F target genes.

Dorner et al. found that cells treated with LAP2 RNAi proliferated more rapidly than untreated controls. Cells with excess LAP2, however, paused at the G1-S transition, delayed reentry into the cell cycle after serum addition to previously starved cells and, in preadipocytes, underwent a partial cell cycle arrest and initiation of the differentiation program, including up-regulation of A-type lamins.

Dorner et al. found that LAP2 bound to A-type lamins and hypophosphorylated Rb in immunoprecitates, as well as to several E2F-dependent promoter regions. Cell cycle control by LAP2 required Rb, but the exact mechanism by which LAP2 promotes Rb's transcriptional repressor activity remains unclear.

Previously, researchers hypothesized that laminopathies, which tend to be late onset disorders, were due to reduced structural integrity of cells, which led to tissue degeneration. Now, Dorner et al. think that disruption of the lamin-LAP2 complex by mutations in the lamin genes, such as the ones that cause laminopathies, prevents stem cell differentiation. Without differentiation, tissues lack the cells they need to regenerate and, over the course of an individual's lifetime, the tissues deteriorate. The team, along with several collaborators, has already started to test the new model in LAP2 knock-out and transgenic mice.

Rabiya S. Tuma

rabiya{at}nasw.org

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This Article Full Text (PDF, 1652K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tuma, R. S. Search for Related Content PubMed Articles by Tuma, R. S. Social Bookmarking                      What's this?