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Key cellular processes like gene transcription and DNA replication are facilitated by eukaryotic chromosomes which undergo dynamic assembly and remodelling. A novel ATP-dependent remodelling activity has been identified, and its functional characteristics have been examined. The complex identified has been described as a nucleosome remodelling and deactylating complex. A functional and physical links has been established between nucleosome remodelling proteins and different histone deacetylase chromatin-modifying activities.

Biochemical studies of yeast showed that the transcription initiation apparatus, RNA polymerase II holoenzyme, consists of RNA polymerase II and the SRB (suppressor of RNA polymerase B) regulatory proteins SWI and SNF gene products. Analysis of the proteins identified four classes: SWI2/SNF2, SWI3, SNF5 and SNF11. These regulatory proteins provide the disruption of nucleosomal DNA that promotes activator and TATA-box binding to the nucleosomal DNA transcription initiation promoter sites.

Activation of the transcription factor G box-binding factor (GBF) gene requires exogenous cAMP signaling pathway to initiate the expression of postaggregative or cell type-specific genes. Expression of GBF is induced by cAMP through cell surface receptors. At high cAMP levels, the G alpha2-null subunit of the G protein bypass the cell aggregation stage and forms fruiting bodies. The results suggest that these surface cell receptors are responsible for controlling cell-type differentiation and aggregation in the pathway.

Cytotoxic molecules can kill cancer cells by disrupting critical cellular processes or by inducing novel activities. 6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP) is a small molecule that kills cancer cells by generation of novel activity. DNMDP induces complex formation between phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12) and specifically kills cancer cells expressing elevated levels of these two proteins. Here, we examined the characteristics and covariates of the cancer cell response to DNMDP. On average, the sensitivity of human cancer cell lines to DNMDP is correlated with PDE3A expression levels. However, DNMDP could also bind the related protein, PDE3B, and PDE3B supported DNMDP sensitivity in the absence of PDE3A expression. Although inhibition of PDE3A catalytic activity did not account for DNMDP sensitivity, we found that expression of the catalytic domain of PDE3A in cancer cells lacking PDE3A is sufficient to confer sensitivity to DNMDP, and substitutions in the PDE3A active site abolish compound binding. Moreover, a genome-wide CRISPR screen identified the aryl hydrocarbon receptor-interacting protein (AIP), a co-chaperone protein, as required for response to DNMDP. We determined that AIP is also required for PDE3A-SLFN12 complex formation. Our results provide mechanistic insights into how DNMDP induces PDE3A-SLFN12 complex formation, thereby killing cancer cells with high levels of PDE3A and SLFN12 expression. [ABSTRACT FROM AUTHOR]

Background--Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits atherosclerosis. These effects are mediated by estrogen receptors (ERs), which, when bound to estrogen, can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a rapid nonnuclear signaling cascade. However, the biological significance of this rapid signaling pathway has been unclear. Methods and Results--In the present study, we develop a novel transgenic mouse in which rapid signaling is blocked by overexpression of a peptide that prevents ERs from interacting with the scaffold protein striatin (the disrupting peptide mouse). Microarray analysis of ex vivo treated mouse aortas demonstrates that rapid ER signaling plays an important role in estrogen-mediated gene regulatory responses. Disruption of ER-striatin interactions also eliminates the ability of estrogen to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth. The importance of these findings is underscored by in vivo experiments demonstrating loss of estrogen-mediated protection against vascular injury in the disrupting peptide mouse after carotid artery wire injury. Conclusions--Taken together, these results support the concept that rapid, nonnuclear ER signaling contributes to the transcriptional regulatory functions of ER and is essential for many of the vasoprotective effects of estrogen. These findings also identify the rapid ER signaling pathway as a potential target for the development of novel therapeutic agents. [ABSTRACT FROM AUTHOR]