From its discovery as a phosphatidylethanolamine-binding protein in bovine brain to its designation as a physiological inhibitor of Raf kinase protein, RKIP has emerged as a critical molecule for maintaining subdued, well-orchestrated cellular responses to stimuli. The disruption of RKIP in a wide range of pathologies, including cancer, Alzheimer's disease, and pancreatitis, makes it an exciting target for individualized therapy and disease-specific interventions. This review attempts to highlight recent advances in the RKIP field underscoring its potential role as a master modulator of many pivotal intracellular signaling cascades that control cellular growth, motility, apoptosis, genomic integrity, and therapeutic resistance. Specific biological and functional niches are highlighted to focus future research towards an enhanced understanding of the multiple roles of RKIP in health and disease.

RKIP-1 is a metastasis suppressor that is frequently downregulated in aggressive cancers. However, the consequences of RKIP loss in primary or immortalized cells have not yet been explored. Using HEK-293 RKIP depleted (termed HEK-499) and Flp-In T-Rex-293 RKIP inducible cell lines combined with whole transcriptome analysis, we show that RKIP-1 silencing accelerates DNA synthesis and G1/S transition entry by inducing the expression of cdc6, MCM 2, 4, 6, 7, cdc45L, cyclin D2, cyclin E2, cyclin D1, SKP2 and the downregulation of p21(cip1). Moreover, RKIP depletion accelerates the time from nuclear envelop breakdown (NEB) to anaphase markedly, while the upregulation of RKIP shortened the NEB to anaphase time. We show that RKIP depletion induces the expression of NEK6, a molecule known to enhance G2/M transition, and down-regulates G2/M checkpoint molecules like Aurora B, cyclin G1 and sertuin that slow the G2/M transition time. These subtle changes in the kinetics of the cell cycle culminate in a higher proliferation rate of HEK-499 compared to control cells. Finally, we show that RKIP depletion enhances cellular motility by inducing the expression/stabilization of β-catenin, vimentin, MET and PAK1. Overall, our data suggest that modulation of the cell cycle checkpoints and motility by RKIP may be fundamental to its metastasis suppressive function in cancer and that RKIP role in a cell is more intricate and diverse than previously thought.

No abstract

Aims: The present study aimed at analyzing prevalence of participation in gambling activities, gambling disorder as well as associated risk factors in the German adult population. Methods: Data came from the 2009 Epidemiological Survey of Substance Abuse (ESA) using a mixed-mode design including questionnaires, telephone and Internet interviews. The cross-sectional random sample consisted of 8,006 subjects aged 18 to 64 years. The response rate was 50.1 %. Results: With a 12-month prevalence of 48.0 %, gambling was a common activity differing by gender (males: 53.9 %, females: 42.0 %). Prevalence of pathological gambling (PG; past 12 months) was estimated at 0.3 % and at 1.1 % for subthreshold pathological gambling (SPG). Various socioeconomic characteristics were related to SPG and/or PG. Male gender and non-German nationality have shown the greatest risk factors for PG. Moreover, gambling frequency and multiple gambling participation were positive associated with SPG and PG. A strong association was found for preference for Internet gambling with SPG and for preference for gaming machines and sports events with PG. Conclusions: The results indicate that SPG was genuinely different from gambling without endorsing any DSM-IV criteria calling for more research on the clinical relevance and classification of this subgroup. Furthermore, findings highlight the need for prevention and intervention measures that target subjects with specific socioeconomic and gambling-related risk factors.

No abstract