Snail is a key regulator of epithelial-mesenchymal transition (EMT), which is a major step in tumor metastasis. Although the induction of Snail transcription precedes EMT, posttranslational regulation, especially phosphorylation of Snail, is critical for determining Snail protein levels or stability, subcellular localization, and the ability to induce EMT. To date, several kinases are known that enhance the stability of Snail by preventing its ubiquitination; however, the molecular mechanism(s) underlying this are still unclear. Here, we identified p38 MAPK as a crucial posttranslational regulator that enhances the stability of Snail. p38 directly phosphorylated Snail at Ser107, and this effectively suppressed DYRK2-mediated Ser104 phosphorylation, which is critical for GSK3b-dependent Snail phosphorylation and bTrCP-mediated Snail ubiquitination and degradation. Importantly, functional studies and analysis of clinical samples established a crucial role for the p38-Snail axis in regulating ovarian cancer EMT and metastasis. These results indicate the potential therapeutic value of targeting the p38-Snail axis in ovarian cancer. Significance: These findings identify p38 MAPK as a novel regulator of Snail protein stability and potential therapeutic target in ovarian cancer.

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These results suggest that HP0425 carrying a nuclear localization signal sequence translocates into the nucleus of host cells and degrades genomic DNA by DNase I-like enzymatic activity, which is a new pathogenic strategy of H. pylori in the host.

BackgroundIn higher primates, during non-pregnant cycles, it is indisputable that circulating LH is essential for maintenance of corpus luteum (CL) function. On the other hand, during pregnancy, CL function gets rescued by the LH analogue, chorionic gonadotropin (CG). The molecular mechanisms involved in the control of luteal function during spontaneous luteolysis and rescue processes are not completely understood. Emerging evidence suggests that LH/CGR activation triggers proliferation and transformation of target cells by various signaling molecules as evident from studies demonstrating participation of Src family of tyrosine kinases (SFKs) and MAP kinases in hCG-mediated actions in Leydig cells. Since circulating LH concentration does not vary during luteal regression, it was hypothesized that decreased responsiveness of luteal cells to LH might occur due to changes in LH/CGR expression dynamics, modulation of SFKs or interference with steroid biosynthesis.MethodsSince, maintenance of structure and function of CL is dependent on the presence of functional LH/CGR its expression dynamics as well as mRNA and protein expressions of SFKs were determined throughout the luteal phase. Employing well characterized luteolysis and CL rescue animal models, activities of SFKs, cAMP phosphodiesterase (cAMP-PDE) and expression of SR-B1 (a membrane receptor associated with trafficking of cholesterol ester) were examined. Also, studies were carried out to investigate the mechanisms responsible for decline in progesterone biosynthesis in CL during the latter part of the non-pregnant cycle.Results and discussionThe decreased responsiveness of CL to LH during late luteal phase could not be accounted for by changes in LH/CGR mRNA levels, its transcript variants or protein. Results obtained employing model systems depicting different functional states of CL revealed increased activity of SFKs [pSrc (Y-416)] and PDE as well as decreased expression of SR-B1correlating with initiation of spontaneous luteolysis. However, CG, by virtue of its heroic efforts, perhaps by inhibition of SFKs and PDE activation, prevents CL from undergoing regression during pregnancy.ConclusionsThe results indicated participation of activated Src and increased activity of cAMP-PDE in the control of luteal function in vivo. That the exogenous hCG treatment caused decreased activation of Src and cAMP-PDE activity with increased circulating progesterone might explain the transient CL rescue that occurs during early pregnancy.

BackgroundIn several species, considerably higher levels of estradiol-17 (E2) are synthesized in the CL. E2 has been suggested to participate in the regulation of luteal steroidogenesis and luteal cell morphology. In pregnant rats, several experiments have been carried out to examine the effects of inhibition of luteal E2 synthesis on CL structure and function.MethodsDuring days 12–15 of pregnancy in rats, luteal E2 was inhibited by way of daily oral administration of anastrozole (AI), a selective non-steroidal aromatase inhibitor, and experiments were also performed with E2 replacement i.e. AI+ E2 treatments. Luteal tissues from different treatment groups were subjected to microarray analysis and the differentially expressed genes in E2 treated group were further examined for expression of specific E2 responsive genes. Additional experiments were carried out employing recombinant growth hormone preparation and flutamide, an androgen receptor antagonist, to further address the specificity of E2 effects on the luteal tissue.ResultsMicroarray analysis of CL collected on day 16 of pregnancy post AI and AI+E2 treatments showed significantly lowered cyp19a1 expression, E2 levels and differential expression of a number of genes, and several of them were reversed in E2 replacement studies. From the differentially expressed genes, a number of E2 responsive genes were identified. In CL of AI pregnant rats, non-significant increase in expression of igf1, significant increase in igbp5, igf1r and decrease in expression of Erα were observed. In liver of AI treated rats, igf1 expression did not increase, but GH treatment significantly increased expression that was further increased with AI treatment. In CL of GH and AI+GH treated rats, expression of igfbp5 was higher. Administration of flutamide during days 12–15 of pregnancy resulted in non-significant increase in igfbp5 expression, however, combination of flutamide+AI treatments caused increased protein expression. Expression of few of the molecules in PI3K/Akt kinase pathway in different treatments was determined.ConclusionsThe results suggest a role for E2 in the regulation of luteal steroidogenesis, morphology and proliferation. igfbp5 was identified as one the E2 responsive genes with important role in the mediation of E2 actions such as E2-induced phosphorylation of PI3K/Akt kinase pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-016-0153-1) contains supplementary material, which is available to authorized users.