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Editorial
. 2010 Feb 5;106(2):234-7.
doi: 10.1161/CIRCRESAHA.109.212001.

Another broken heart: loss of lamina-associated polypeptide 2alpha causes systolic dysfunction

Valerie L R M Verstraeten, Jan Lammerding
Editorial

Another broken heart: loss of lamina-associated polypeptide 2alpha causes systolic dysfunction

Valerie L R M Verstraeten et al. Circ Res. .
No abstract available

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Figures

Figure 1
Figure 1. Overview of the localization of nuclear (envelope) proteins linked to dilated cardiomyopathy
Schematic depiction of the structural and gene regulatory roles of lamins and other nuclear envelope proteins and their interaction with transcription factors to mediate gene regulation. (Left) In wildtype cells, lamins form a filamentous network, i.e., the lamina, lining the nucleoplasmic side of the nuclear envelope. They space nuclear pore complexes and interact with multiple integral nuclear membrane proteins such as emerin and SUN1/2-proteins. SUN-proteins interact across the perinuclear space with nesprins that can bind to actin stress fibers or, via plectin, to the intermediate filament network, thereby establishing a physical link between the nuclear interior and the cytoskeleton. Shorter nesprin isoforms can also be located on the inner nuclear membrane, where they may bind to lamins and emerin. Emerin, just as most integral Lamina Associated Polypeptide 2 (LAP2) family members, contains a transmembrane domain and a so-called LEM domain through which these proteins bind BAF and, thus, are involved in chromatin organization. Emerin can further bind nuclear actin and signaling factors such as the Drosophila melanogaster germ cell-less gene product (GCL). Lamins also make up a more diffuse network in the nucleoplasm that may serve as a scaffold for multiple transcription factors such as retinoblastoma protein pRb and LAP2α. The phosphatase PP2A dephosphorylates pRb in a complex that involves lamin A/C. It is yet unclear if LAP2α is part of this complex and if a complex of hypophosphorylated pRb-lamin A/C-LAP2α translocates to the E2F-target genes to repress transcription, leading to cell cycle arrest and potentially, DNA repair and differentiation. Cyclin dependent kinases (CDK) can phosphorylate pRb through which it is released from the E2F-target genes, resulting in transcription activation, cell cycle progression and proliferation. (Right) In the absence of LAP2α, lamin A/C is localized predominantly at the nuclear periphery, and pRb remains hyperphosphorylated and, therefore, cannot repress transcription of E2F-target genes. The result is increased proliferation and, potentially, early depletion of progenitor/stem cells. [Figure adapted from and reproduced with permission from Bentham Science Publishers Ltd.]
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Comment on

References

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