生长抑制因子(ING)抑癌基因家族的研究进展

生长抑制因子(inhibitor of growth,ING)家族成员是候选的抑癌基因.ING蛋白参与磷脂酰肌醇介导的脂类信号转导通路及激素介导的通路,能够与组蛋白乙酰转移酶、去乙酰化酶等结合参与染色质的重构,调节基因的转录,与p53协同作用,抑制细胞生长,诱导细胞凋亡和DNA损伤修复.ING家族成员通过对基因表达的表观遗传学调控将细胞周期、细胞凋亡和衰老等生物学过程有机联系起来.     

Cytokinin signaling

Cytokinins influence many aspects of plant growth and development. The current model for cytokinin signaling is a multi-step phosphorelay similar to the prokaryotic two-component systems that are used in responses to environmental stimuli. Recently, progress has been made in improving our understanding of the molecular mechanism that underlies cytokinin signaling. Molecular and genetic analyses of loss-of-function mutants indicate that the two-component elements that are involved in cytokinin signaling have redundant and overlapping functions. These elements regulate both the shoot and root meristems, are required for the development of fertile flowers, and modulate the response to varying nutrient levels.     

Cellular signaling by peptides of the endothelin gene family

Endothelins (ET) are a family of regulatory peptides synthesized by selected endothelial and epithelial cells that act in a paracrine fashion on nearby smooth muscle or connective tissue cells. We review the pathways of transmembrane signaling triggered by binding of endothelin peptides to receptors on the plasma membrane. Although our understanding of many components is unclear, endothelin peptides appear to evoke a phosphoinositide-linked signaling system that bears a striking resemblance to signaling pathways activated by other regulatory peptides. Expression of endothelin receptors and specific pathways stimulated by activated receptors are controlled in a cell- and tissue-specific manner, which perhaps explains the diverse biological actions of endothelin in different tissues. Complex negative feedback pathways regulate endothelin-induced signaling at the receptor and second messenger levels. Moreover, by regulating the activity of sequence-specific DNA binding proteins, short-term signals by ET can be extended to long-term effects involving gene expression. Regulation of gene expression by ET could account for complex events such as mitogenesis and vascular and tissue remodeling in disease.     

Nitric oxide regulated two-component signaling in Pseudoalteromonas atlantica

Bacteria employ two-component signaling to detect and respond to environmental stimuli. In essence, two-component signaling relies on a protein called a response regulator that can elicit a change in gene expression or protein function in response to phosphoryl transfer from a histidine kinase. Phosphorylation of the associated histidine kinase is regulated by detection of an environmental signal, thus linking sensing to cellular response. Recently, it has been suggested that H-NOX (Heme-nitric oxide/oxygen binding) proteins may act as nitric oxide (NO) sensors in two-component signaling systems. NO/H-NOX regulated histidine kinases have been reported, but their cognate response regulators have yet to be identified. In this work we provide biochemical characterization of a complete NO/H-NOX-regulated two-component signaling pathway in the biofilm-dwelling marine bacterium, Pseudoalteromonas atlantica. In P. atlantica, as is typical for bacteria that code for H-NOX, an hnoX gene is found in the same operon as a gene coding for a two-component signaling histidine kinase (H-NOX-associated histidine kinase; HahK). We find that HahK is capable of autophosphorylation in vitro and that NO-bound H-NOX inhibits HahK activity, implicating H-NOX as a selective NO sensor. The cognate response regulator, a protein annotated as a cyclic-di-GMP processing enzyme that we have named HarR (H-NOX-associated response regulator), was identified using bioinformatics tools. Phosphoryl transfer from HahK to HarR has been established. This report reveals the first biochemical characterization of an H-NOX-associated response regulator and contributes to a deeper understanding of NO/H-NOX signaling in bacteria.     

Two-component systems in Arabidopsis thaliana – A structural view

Plants respond to outside stimuli by initiating signaling cascades that regulate gene expression. Little structural information is available on the signaling proteins that are part of the two-component systems of plants, and how changes in phosphorylation translate into alterations of three-dimensional structures and changes in recognition domains remains largely mysterious. Our work is on deciphering aspects of these systems through the crystallization and structural analysis of two-component system proteins in Arabidopsis thaliana.     

Argonaute Proteins and Mechanisms of RNA Interference in Eukaryotes and Prokaryotes

Noncoding RNAs play essential roles in genetic regulation in all organisms. In eukaryotic cells, many small non-coding RNAs act in complex with Argonaute proteins and regulate gene expression by recognizing complementary RNA targets. The complexes of Argonaute proteins with small RNAs also play a key role in silencing of mobile genetic elements and, in some cases, viruses. These processes are collectively called RNA interference. RNA interference is a powerful tool for specific gene silencing in both basic research and therapeutic applications. Argonaute proteins are also found in prokaryotic organisms. Recent studies have shown that prokaryotic Argonautes can also cleave their target nucleic acids, in particular DNA. This activity of prokaryotic Argonautes might potentially be used to edit eukaryotic genomes. However, the molecular mechanisms of small nucleic acid biogenesis and the functions of Argonaute proteins, in particular in bacteria and archaea, remain largely unknown. Here we briefly review available data on the RNA interference processes and Argonaute proteins in eukaryotes and prokaryotes.     

The family of organo-phosphate transport proteins includes a transmembrane regulatory protein

This review article briefly summarizes aspects of our current understanding of the Uhp sugar phosphate transport system in enteric bacteria, particularly the mode of genetic regulation of its synthesis. This regulation occurs by a process that involves an example of the very widespread and ever-growing group of so-called two-component bacterial regulatory systems, a mechanism of response to environmental signals that employs phosphate transfer reactions between constituent proteins. Of emphasis here is the unusual involvement in transmembrane signaling of the UhpC protein which is related in sequence and structure to some transport proteins, including the very protein whose synthesis it helps regulate.     

Comprehensive DNA microarray analysis of Bacillus subtilis two-component regulatory systems.

It has recently been shown through DNA microarray analysis of Bacillus subtilis two-component regulatory systems (DegS-DegU, ComP-ComA, and PhoR-PhoP) that overproduction of a response regulator of the two-component systems in the background of a deficiency of its cognate sensor kinase affects the regulation of genes, including its target ones. The genome-wide effect on gene expression caused by the overproduction was revealed by DNA microarray analysis. In the present work, we newly analyzed 24 two-component systems by means of this strategy, leaving out 8 systems to which it was unlikely to be applicable. This analysis revealed various target gene candidates for these two-component systems. It is especially notable that interesting interactions appeared to take place between several two-component systems. Moreover, the probable functions of some unknown two-component systems were deduced from the list of their target gene candidates. This work is heuristic but provides valuable information for further study toward a comprehensive understanding of the B. subtilis two-component regulatory systems. The DNA microarray data obtained in this work are available at the KEGG Expression Database website (http://www.genome.ad.jp/kegg/expression).     

Role of the serine-threonine kinase PAK-1 in myxoma virus replication

Subversion or appropriation of cellular signal transduction pathways is a common strategy employed by viruses to promote an environment within infected cells that supports the viral replicative cycle. Using subsets of 3T3 murine fibroblasts previously shown to differ in their ability to support myxoma virus (MV) replication, we investigated the role of host serine-threonine kinases (STKs) as potential mediators of the permissive phenotype. Both permissive and nonpermissive 3T3 cells supported equivalent levels of virion binding, entry, and early virus gene expression, indicating that MV tropism in 3T3 cells was not determined by receptor-mediated entry. In contrast, late virus gene expression and viral DNA replication were selectively compromised in restrictive 3T3 cells. Addition of specific protein kinase inhibitors, many of which shared the ability to influence the activity of the STKs p21-activated kinase 1 (PAK-1) and Raf-1 attenuated MV replication in permissive 3T3 cells. Western blot detection of the phosphorylated forms of PAK-1 (Thr423) and Raf-1 (Ser338) confirmed activation of these kinases in permissive cells after MV infection or gamma interferon treatment, but the activated forms of both kinases were greatly reduced or absent in restrictive 3T3 cells. The biological significance of these activations was demonstrated by using the autoinhibitory domain of PAK-1 (amino acids 83 to 149), expression of which reduced the efficiency of MV infection in permissive 3T3 cells concurrent with a decrease in PAK-1 activation. In comparison, overexpression of a constitutively active PAK-1 (T423E) mutant increased MV replication in restrictive 3T3 cells. These observations suggest that induced signaling via cellular STKs may play important roles in determining the permissiveness of host cells to poxvirus infection.     

Rewiring two-component signal transduction with small RNAs

Bacterial two-component systems (TCSs) and small regulatory RNAs (sRNAs) form densely interconnected networks that integrate and transduce information from the environment into fine-tuned changes of gene expression. Many TCSs control target genes indirectly through regulation of sRNAs, which in turn regulate gene expression by base-pairing with mRNAs or targeting a protein. Conversely, sRNAs may control TCS synthesis, thereby recruiting the TCS regulon to other regulatory networks. Several TCSs control expression of multiple homologous sRNAs providing the regulatory networks with further flexibility. These sRNAs act redundantly, additively or hierarchically on targets. The regulatory speed of sRNAs and their unique features in gene regulation make them ideal players extending the flexibility, dynamic range or timing of TCS signaling.