Anchoring proteins encounter mitotic kinases

Howard Hughes Medical Institute
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 03/2013; 12(6). DOI: 10.4161/cc.24192
Source: PubMed
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    • "Therefore, the dual effect of YTX over tumor and non-tumor cells point to this compound as a powerful antitumoral drug or at least as a good drug lead [75,76]. In this sense, AKAP 149 protein is essential for mitosis777879, hence those factors that prevent the activity of this protein cause cell death, as in the case of YTX in K-526 cells. This line of reasoning based on AKAP 149 would explain the differences in response between normal and tumor cells to YTX. "
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    • "These cancers can be exacerbated by mislocalization or misregulation of mitogenic and mitotic protein kinase cascades (Carnegie et al., 2009; Scott and Pawson, 2009). The A-kinase anchoring protein Gravin/AKAP12/ SSeCKS has been implicated in the control of mitotic progression (Xia et al., 2001; Gelman, 2010; Canton et al., 2012; Canton and Scott, 2013). We now report that Gravin is depleted in proliferating germ line-derived tumors from several patients diagnosed with testicular seminoma. "
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    ABSTRACT: Correct orientation of the mitotic spindle in stem cells underlies organogenesis. Spindle abnormalities correlate with cancer progression in germ line-derived tumors. We discover a macromolecular complex between the scaffolding protein Gravin/AKAP12 and the mitotic kinases, Aurora A and Plk1, that is down regulated in human seminoma. Depletion of Gravin correlates with an increased mitotic index and disorganization of seminiferous tubules. Biochemical, super-resolution imaging, and enzymology approaches establish that this Gravin scaffold accumulates at the mother spindle pole during metaphase. Manipulating elements of the Gravin-Aurora A-Plk1 axis prompts mitotic delay and prevents appropriate assembly of astral microtubules to promote spindle misorientation. These pathological responses are conserved in seminiferous tubules from Gravin−/− mice where an overabundance of Oct3/4 positive germ line stem cells displays randomized orientation of mitotic spindles. Thus, we propose that Gravin-mediated recruitment of Aurora A and Plk1 to the mother (oldest) spindle pole contributes to the fidelity of symmetric cell division.
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    ABSTRACT: Background: Key challenges of biopsy-based determination of prostate cancer aggressiveness include tumour heterogeneity, biopsy-sampling error, and variations in biopsy interpretation. The resulting uncertainty in risk assessment leads to significant overtreatment, with associated costs and morbidity. We developed a performance-based strategy to identify protein biomarkers predictive of prostate cancer aggressiveness and lethality regardless of biopsy-sampling variation. Methods: Prostatectomy samples from a large patient cohort with long follow-up were blindly assessed by expert pathologists who identified the tissue regions with the highest and lowest Gleason grade from each patient. To simulate biopsy-sampling error, a core from a high- and a low-Gleason area from each patient sample was used to generate a 'high' and a 'low' tumour microarray, respectively. Results: Using a quantitative proteomics approach, we identified from 160 candidates 12 biomarkers that predicted prostate cancer aggressiveness (surgical Gleason and TNM stage) and lethal outcome robustly in both high- and low-Gleason areas. Conversely, a previously reported lethal outcome-predictive marker signature for prostatectomy tissue was unable to perform under circumstances of maximal sampling error. Conclusions: Our results have important implications for cancer biomarker discovery in general and development of a sampling error-resistant clinical biopsy test for prediction of prostate cancer aggressiveness.
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