PerspectiveCell Signaling

Nuclear Actin as Choreographer of Cell Morphology and Transcription

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Science  22 Jun 2007:
Vol. 316, Issue 5832, pp. 1710-1711
DOI: 10.1126/science.1145014

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Cellular responses to environmental stimuli often require coordination of rapid changes in cell shape with reprogramming of gene expression. However, relatively little has been known about how these essential events in different parts of the cell are harmonized. On page 1749 of this issue (1), Vartiainen et al. reveal an exciting new mechanism underlying this coordination, involving interactions between the actin cytoskeleton and a protein that regulates gene expression, called MAL.

Many mammalian cells respond to serum (which contains growth factors and other stimuli) by changing their morphology and activating gene expression through the serum response factor. The target genes of this transcription factor include those involved in cell growth, proliferation, and differentiation, as well as genes that control the actin cytoskeleton. Remarkably, serum response factor activity mirrors the state of cellular actin; a decrease in monomeric actin (G-actin) is both necessary and sufficient for serum response factor to activate gene expression (2). But how are changes in the amount of cellular G-actin communicated to the nucleus?

G-actin has dual residence in a cell. In the cytoplasm, it participates in a dynamic process of polymerization and depolymerization, generating actin filaments (F-actin) that can cause a cell's shape to change (see the figure). But G-actin also shuttles into and out of the nucleus, where it is thought to regulate chromatin structure and transcription. Prior to serum stimulation, MAL—a myocardin family transcriptional coactivator for serum response factor (2)—resides in the cytoplasm, where it interacts with G-actin. However, upon serum stimulation, F-actin forms to produce stress fibers in the cytoplasm, and G-actin levels decrease correspondingly. Sensing depletion of the G-actin pool, MAL dissociates from G-actin, and Vartiainen et al. show that this causes the already high basal rate of MAL import into the nucleus to increase.

An actin circuit.

Filamentous actin (F-actin) and monomeric actin (G-actin) pools are regulated by various signals triggered by growth factors and other stimuli present in serum. Signals that enhance actin polymerization cause MAL to move into the nucleus. Vartiainen et al. show that MAL is regulated by nuclear G-actin at multiple steps, as shown. SRF, serum response factor.

CREDIT: P. HUEY/SCIENCE

In addition to a role in nuclear import, Vartiainen et al. demonstrate surprising roles for G-actin in regulating the export of MAL from the nucleus and in controlling the activation of serum response factor. MAL also binds to G-actin in the nucleus, and Vartiainen et al. show that this association is required for MAL to exit the nucleus. Thus, one would predict that after serum stimulation, a reduction of cytoplasmic G-actin (the cost of making F-actin) causes MAL to accumulate in the nucleus, thereby increasing MAL-dependent transcription. This indeed appears to be the case, but the explanation is more complex.

The authors show that nuclear accumulation alone is not enough for MAL to activate the expression of target genes by serum response factor. When MAL is prevented from exiting the nucleus (for example, by treating cells with the drug leptomycin B, which inhibits the cell's nuclear export machinery), the complex of MAL-serum response factor is transcriptionally inactive, even though it is poised on the promoters of target genes (shown by chromatin immunoprecipitation). Repression of serum response factor-dependent transcription is relieved by serum-induced actin polymerization in the cytoplasm, which depletes cytoplasmic G-actin. Because G-actin shuttles between the nucleus and the cytoplasm, events that promote actin polymerization in the cytoplasm also deplete nuclear G-actin (see the figure). Vartiainen et al. show that depletion of nuclear G-actin derepresses the expression of genes that require MAL for transcription by both reducing the rate of nuclear export of MAL and restoring MAL's ability to activate transcription after binding to target genes. This raises the question of how transcription by serum response factor is blocked by G-actin interaction with MAL in the nucleus.

One possible explanation is that G-actin binding to MAL in the nucleus does not permit assembly of an effective transcription complex. Serum response factor lies at the nexus of two major signaling pathways that control the expression of different genes. One pathway involves the signaling enzyme MAP kinase and the activation of transcription coactivators of the ternary complex factor family (3). The other pathway relies on the myocardin family of coactivators (to which MAL belongs) (4). Because both families of coactivators bind to the same region of serum response factor, the G-actin-MAL complex may have reduced affinity for serum response factor. Another possible explanation relates to chromatin regulation by G-actin. In yeast and mammalian cells, G-actin is present in a number of protein complexes that remodel chromatin (5), enhancing adenosine triphosphatase activity of these complexes (6). It has been estimated that 10% of total nuclear Gactin is associated with SWI/SNF-like BAF chromatin-remodeling complexes. G-actin in these complexes may interact with MAL, physically linking MAL function to that of the remodeling complexes (inhibiting transcription), presumably by forming chromatin structures that repress gene expression. However, MAL has not been found associated with chromatin-remodeling complexes, making this explanation less attractive. A more likely explanation of how transcription by serum response factor is blocked by the MAL-G-actin complex is that G-actin simply interferes with MAL association with components of the general transcription apparatus, thus preventing serum response factor from activating transcription.

Skeptics might argue that many mechanisms elaborated in cultured cells may only be true of the cell line, with its specific chromosomal breakages, DNA methylation patterns, and thereby altered genetic circuits. This is almost certainly not the case with the work by Vartiainen et al. Although the authors used fibroblast cell lines, aspects of their mechanism are supported by rigorous genetic studies in mice. For example, deletion of the serum response factor gene in mice leads to death of embryos at gastrulation (7), when both transcription and actin-induced cell movement are essential. Conditional deletion of serum response factor in the murine nervous system produces specific defects in neurite outgrowth and neuron migration that are linked to reduced expression of actin and its regulators (8, 9). Finally, mice genetically engineered to lack MAL have defects in myoepithelial cell differentiation (10).

Cell biologists have long thought of actin regulation in the context of controlling cell morphology and movement. However, if confirmed by additional genetic studies (for example, analysis of mice with mutations in MAL that block its interaction with actin), the work by Vartiainen et al. elucidates how actin choreographs the regulation of morphology and transcription. Such a coordinated genetic circuitry must underlie such diverse events as early embryonic development, neuron migration, blood vessel formation, and lymphocyte signaling.

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