Nuclear Actin‐Binding Proteins as Modulators of Gene Transcription

Abstract

Dynamic transformations in the organization of the cellular microfilament system are the driving force behind fundamental biological processes such as cellular motility, cytokinesis, wound healing and secretion. Eukaryotic cells express a plethora of actin-binding proteins (ABPs) allowing cells to control the organization of the actin cytoskeleton in a flexible manner. These structural proteins were, not surprisingly, originally described as (major) constituents of the cytoplasm. However, in recent years, there has been a steady flow of reports detailing not only translocation of ABPs into and out of the nucleus but also describing their role in the nuclear compartment. This review focuses on recent developments pertaining to nucleocytoplasmic transport of ABPs, including their mode of translocation and nuclear function. In particular, evidence that structurally and functionally unrelated cytoplasmic ABPs regulate transcription activation by various nuclear (steroid hormone) receptors is steadily accruing. Furthermore, the recent finding that actin is a necessary component of the RNA polymerase II-containing preinitiation complex opens up new opportunities for nuclear ABPs in gene transcription regulation.Key words: actin-binding protein, actin, cytoskeleton, gene transcription, nucleus, steroid hormone receptor, transcription factor, transport Nucleocytoplasmic TransportIn eukaryotic cells, the cytoplasm and nucleus are separated by the nuclear envelope. Trafficking of proteins and RNA molecules across this double membrane occurs via the nuclear pore complex, a large proteinaceous channel embedded in the nuclear membrane and composed of approximately 30 different proteins, termed nucleoporins (1). Protein transport is mediated by soluble transport receptors known as importins and exportins. These proteins recognize transport signals in their cargoes (Table 1) (2-4) and mediate translocation through the nuclear pore complex, primarily through interactions with nucleoporins. Although several other transport signals have been identified, targeting sequences in many cargoes of importin-b receptors still await identification.The best known nuclear export signal is a leucine-rich sequence that was first identified in the HIV-1 Rev protein (5,6) and protein kinase A inhibitor (7). These signals are recognized by the CRM1 receptor, a member of the importin-b family. Binding of CRM1 to leucine-rich export sequences is inhibited by leptomycin B, an antifungal antibiotic isolated from Streptomyces spieces (5,8), and has become a useful tool to identify

Dynamics of the CapG actin-binding protein in the cell nucleus studied by FRAP and FCS

“…Furthermore, an interaction with steroid receptors is possible, which is reported with respect to other Gelsolin-related proteins (Gettemans et al 2005).…”

“…There is no typical nuclear localization signal (NLS), rather several regions of different subdomains are responsible for nuclear import (Gettemans et al 2005). In contrast to the other Gelsolin-related actin-binding proteins the CapG protein lacks a nuclear export sequence (van Impe et al 2003).…”

“…Units larger than the mesh size, e.g. PML bodies, can also move through the nucleus by a combination of local random motion and longer-distance Fjumps_ (Goerisch et al 2005); in this case, the dynamics of the chromatin network itself have a fundamental role in the mobility of such complexes.…”

Invasive breast cancer cells exhibit increased mobility of the actin‐binding protein CapG

“…1 There is no typical nuclear localization signal (NLS), rather several regions of different subdomains are responsible for the nuclear import. 2 A couple of positively charged amino acids within the PIP 2 -binding region of the CapG protein or the amino acids 134-147, respectively, are proposed as potential equivalents of the canonical NLS. 3 , 4 In contrast to the other Gelsolin-related actin-binding proteins, the CapG protein lacks a nuclear export sequence, especially the decisive leucines 5 (L17, L21, L27).…”

“…The founding member of the protein family, Gelsolin, modulates the transcriptional activity of PPAR-g, and in response to stimulation by the ligand that of the androgen and glucocorticoid receptor; 19 other members of the protein family are reported to interact with various steroid receptors. 2 Recent studies hint at the fact that the CapG fraction that is localized within the cell nucleus is crucial for cell motility, or rather for the increase in motility of benign cells:…”