Nuclear Distribution of Prothymosin α and Parathymosin: Evidence That Prothymosin α Is Associated with RNA Synthesis Processing and Parathymosin with Early DNA Replication

Vareli, Katerina; Frangou-Lazaridis, Maria; Kraan, K. van der; Tsolas, Orestes; Driel, Roel van

doi:10.1006/excr.2000.4857

Cited by 38 publications

(40 citation statements)

References 68 publications

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“…It has been demonstrated that ProT exhibits a punctuated nuclear distribution, which is related to that of transcription sites, implying that ProT is involved in transcription. 17 Our results from the distribution of the ProT-EGFP fusion protein in MBT-2 cells confirm the nuclear localization of ProT. Furthermore, we also found that the exclusive nuclear localization of ProT could be disturbed by deleting its NLS.…”

Section: Discussionsupporting

confidence: 84%

Retrovirus-mediated transfer of prothymosin gene inhibits tumor growth and prolongs survival in murine bladder cancer

et al. 2001

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Section: Discussionsupporting

confidence: 84%

Retrovirus-mediated transfer of prothymosin gene inhibits tumor growth and prolongs survival in murine bladder cancer

et al. 2001

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“…Under these conditions, polymer effects characteristic of the semidilute regime will be highly relevant for the conformations of IDPs and for the occurrence of possible phase transitions. Interestingly, ProTα often colocalizes with dense speckles such as promyelocytic leukemia bodies (52). Given its abundance in the nucleus of mammalian cells and its high mobility within and near the nucleus (53), we expect that a compaction similar to what we observed here can occur in vivo.…”

Section: Discussionsupporting

confidence: 63%

Single-molecule spectroscopy reveals polymer effects of disordered proteins in crowded environments

Soranno

Koenig

Borgia

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

233

307

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Intrinsically disordered proteins (IDPs) are involved in a wide range of regulatory processes in the cell. Owing to their flexibility, their conformations are expected to be particularly sensitive to the crowded cellular environment. Here we use single-molecule Förster resonance energy transfer to quantify the effect of crowding as mimicked by commonly used biocompatible polymers. We observe a compaction of IDPs not only with increasing concentration, but also with increasing size of the crowding agents, at variance with the predictions from scaled-particle theory, the prevalent paradigm in the field. However, the observed behavior can be explained quantitatively if the polymeric nature of both the IDPs and the crowding molecules is taken into account explicitly. Our results suggest that excluded volume interactions between overlapping biopolymers and the resulting criticality of the system can be essential contributions to the physics governing the crowded cellular milieu. A surprisingly large number of eukaryotic proteins either contain substantial unstructured regions or are entirely unfolded under physiological conditions (1, 2). These "intrinsically disordered proteins" (IDPs) are involved in many crucial cellular processes, such as transcription, translation, and signal transduction; their functional and conformational properties are thus of great interest for a wide range of biological questions. Important advances in understanding the structures of IDPs have been made over the past decade, especially with spectroscopic techniques, e.g., NMR (3, 4), single-molecule fluorescence (5-7), and with atomistic and coarse-grained molecular simulations (8-10). In contrast with the stable folded structures we are familiar with from 50 y of structural biology, IDPs comprise highly heterogeneous and dynamic ensembles of conformations, which either lack stable tertiary structure altogether or fold only on binding their cellular targets (4). Important components of the cellular environment that affect IDPs include not only specific cellular ligands, but also pH and the concentration of salts (11,12). An additional contribution that has been difficult to investigate experimentally comes from the large number of different solutes present in a cell that do not interact with an IDP specifically, but result in an environment that is densely filled with macromolecules and metabolites (12)(13)(14). Given their lack of persistent structure, the conformations of IDPs are expected to be particularly sensitive to the effects of such molecular crowding. Indeed, first experiments indicate that some IDPs gain structure upon crowding (15), whereas others do not (16-18), but may change their dimensions (19)(20)(21). The question of how the conformational distributions of IDPs respond to crowded environments is of particular current interest because IDPs have a vital role in cellular compartments and regions with very high local concentrations of proteins and RNA, such as RNA granules and nuclear pore complexes (22)(23)(24)(25). Howeve...

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“…ParaT Is Localized in Distinct Nuclear Foci-Previous work has shown that ParaT is a nuclear protein associated with early replication domains, suggesting a role of this acidic polypeptide in active chromatin (39). Confocal laser scanning microscopy using affinity-purified antibodies against the NH 2 -terminal region of ParaT revealed a nuclear punctuate staining of the endogenous protein in interphase cells (Fig.…”

Section: Resultsmentioning

confidence: 79%

Parathymosin Affects the Binding of Linker Histone H1 to Nucleosomes and Remodels Chromatin Structure

Martic

Karetsou

Kefala

et al. 2005

Journal of Biological Chemistry

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Linker histone H1 is the major factor that stabilizes higher order chromatin structure and modulates the action of chromatin-remodeling enzymes. We have previously shown that parathymosin, an acidic, nuclear protein binds to histone H1 in vitro and in vivo. Confocal laser scanning microscopy reveals a nuclear punctuate staining of the endogenous protein in interphase cells, which is excluded from dense heterochromatic regions. Using an in vitro chromatin reconstitution system under physiological conditions, we show here that parathymosin (ParaT) inhibits the binding of H1 to chromatin in a dose-dependent manner. Consistent with these findings, H1-containing chromatin assembled in the presence of ParaT has reduced nucleosome spacing. These observations suggest that interaction of the two proteins might result in a conformational change of H1. Fluorescence spectroscopy and circular dichroism-based measurements on mixtures of H1 and ParaT confirm this hypothesis. Human sperm nuclei challenged with ParaT become highly decondensed, whereas overexpression of green fluorescent protein-or FLAG-tagged protein in HeLa cells induces global chromatin decondensation and increases the accessibility of chromatin to micrococcal nuclease digestion. Our data suggest a role of parathymosin in the remodeling of higher order chromatin structure through modulation of H1 interaction with nucleosomes and point to its involvement in chromatindependent functions.Eukaryotic DNA is packaged into chromatin (1), a structural framework that plays a key role in the regulation of the transcriptional status of genes and genetic loci (2-4). The basic level of chromatin organization is the nucleosome that consists of DNA wrapped around an octamer of histones (5). Linker histones (e.g. H1 and H5) seal the entry/exit of DNA and stabilize the folding of 10-nm nucleosomal arrays into higher order chromatin structures (6, 7). Binding of histone H1 to nucleosomal arrays affects the spacing of nucleosomes (8), restricts their mobility (9), and reduces the transient exposure of DNA on the nucleosome surface (10). Consistent with its structural role as a major determinant of chromatin folding, histone H1 was found to inhibit the action of enzymes that enhance the accessibility of DNA, such as histone acetyltransferases and ATP-dependent remodeling complexes. For example, changes in linker histone stoichiometry modulate the levels of core histone acetylation (11) and regulate the activity of all classes of ATP-dependent remodeling enzymes (12, 13). Collectively, these findings support the notion that H1 "locks down" chromatin regions and acts as a general inhibitor of transcription (14, 15). However, genetic studies have shown that, rather than being global repressors of transcription, linker histones affect the expression of specific genes (16). Multiple isoforms of linker histone H1 exist in mammalian somatic cells (17) and play differential roles in gene expression (18). Recently, two independent studies highlight the important role of H1 subtypes in dev...

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Nuclear Distribution of Prothymosin α and Parathymosin: Evidence That Prothymosin α Is Associated with RNA Synthesis Processing and Parathymosin with Early DNA Replication

Cited by 38 publications

References 68 publications

Retrovirus-mediated transfer of prothymosin gene inhibits tumor growth and prolongs survival in murine bladder cancer

Retrovirus-mediated transfer of prothymosin gene inhibits tumor growth and prolongs survival in murine bladder cancer

Single-molecule spectroscopy reveals polymer effects of disordered proteins in crowded environments

Parathymosin Affects the Binding of Linker Histone H1 to Nucleosomes and Remodels Chromatin Structure

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