No abstract

Telomere length is critical for chromosome stability that affects cell proliferation and survival. Telomere elongation by telomerase is inhibited by the telomeric protein, TRF1. Tankyrase-1 (TNKS1) poly(ADP-ribosyl)ates TRF1 and releases TRF1 from telomeres, thereby allowing access of telomerase to the telomeres. TNKS1-mediated poly(ADP-ribosyl)ation also appears to be crucial for regulating the mitotic cell cycle. In searching for proteins that interact with polo-like kinase-1 (Plk1) by using complex proteomics, we identified TNKS1 as a novel Plk1-binding protein. Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends. Taken together, our results provide evidence of a novel molecular mechanism in which phosphorylation of TNKS1 by Plk1 may help regulate mitotic spindle assembly and promote telomeric chromatin maintenance.

Objective: The aim of this study was to diagnose microvascular invasion in patients with solitary hepatocellular carcinoma (HCC) from pre-operative CT imaging. Methods: 102 patients with solitary HCC who underwent curative hepatectomy were retrospectively included in our study. The pre-operative 3-phase CT imaging and laboratory data for the 102 patients were reviewed. Tumour size, tumour margin, peritumoral enhancement and a-fetoprotein level were assessed. Surgical pathology was reviewed; tumour differentiation, liver fibrosis score and microvascular invasion were recorded. Results: The histopathological results revealed that 50 HCCs were positive and the other 52 were negative for microvascular invasion. Univariate analysis revealed that tumour size (p50.036), higher Edmondson-Steiner grade (p50.047) and non-smooth tumour margin (p,0.001) showed statistically significant associations with microvascular invasion. Multivariate logistic regression analysis showed that non-smooth tumour margin had a statistically significant association with microvascular invasion only (p,0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the non-smooth tumour margin in the prediction of microvascular invasion were 66%, 86.5%, 82.5% and 72.6%, respectively. Conclusion: Non-smooth tumour margin in pre-operative CT had a statistically significant association with microvascular invasion. More aggressive treatment should be considered in HCC patients with suspected positive microvascular invasion. Hepatic resection is a potentially curative treatment modality for patients with hepatocellular carcinoma (HCC) [1][2][3][4]. Histopathological vascular tumour invasion is a well-known major prognostic factor for patients with HCC who have undergone hepatic resection or liver transplantation [5][6][7][8]. Iwatsuki et al [9] reported that microvascular and macrovascular invasions were associated with a 4.4-and 15-fold increased risk of recurrence, respectively, for patients who had undergone liver transplantation. Because microvascular tumour invasion has a significant impact on recurrence and prognosis, preoperative diagnosis of microvascular invasion is needed.Radiological detection of microvascular tumour invasion may facilitate the pre-operative prediction of a patient's prognosis. Many researchers have tried to elucidate microvascular invasion based on pre-operative imaging studies, including CT during hepatic angiography, dynamic MRI and superparamagnetic iron oxideenhanced MRI [10][11][12][13]. However, radiological findings suggestive of microvascular invasion in pre-operative CT have not yet been well established. The purpose of our study was to diagnose microvascular invasion in patients with solitary HCC from pre-operative triphasic CT findings. Methods and materials PatientsApproval for retrospective study was obtained from our institutional review board. Between January 2007 and December 2009, 153 patients with HCC who underwent elective curative hepatectomy in our institution were...

Phosphorylation of the Fas-associated death domain (FADD) protein sensitizes cancer cells to various chemotherapeutics. However, the molecular mechanism underlying chemosensitization by phosphorylated FADD (P-FADD) is poorly understood. In this study, we describe the physical interactions and functional interplay between Polo-like kinase 1 (Plk1) and FADD. Plk1 phosphorylates FADD at Ser-194 in response to treatment with taxol. Overexpression of a phosphorylation-mimicking mutant, FADD S194D, caused degradation of Plk1 in an ubiquitin-independent manner, and delayed cytokinesis, consistent with the expected cellular phenotype of Plk1 deficiency. This demonstrates that Plk1 is regulated via a negative feedback loop by its substrate, FADD. Overexpression of FADD S194D sensitized HeLa cells to a low dose of taxol independently of caspase activation, whereas overexpression of FADD S194D resulted in caspase activation in response to a high dose of taxol. Therefore, we examined whether the death potential of P-FADD affected Plk1-mediated tumorigenesis. Transfection of FADD S194D inhibited colony formation by Plk1-overexpressing HeLa cells (HeLa-Plk1). Moreover, overexpression of FADD S194D suppressed tumorigenesis in nude mice xenografted with HeLa-Plk1. Therefore, this study reports the first in vivo validation of tumor-suppressing activity of P-FADD. Collectively, our data demonstrate that in response to taxol, Plk1 endows death-promoting and tumor-suppressor functions to its substrate, FADD.