CK2 Is the Regulator of SIRT1 Substrate-Binding Affinity, Deacetylase Activity and Cellular Response to DNA-Damage

SIRT1, an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase, protects cells from stress-induced apoptosis, and its orthologues delay aging in lower eukaryotes. SIRT1 increases survival in response to stress such as DNA damage by deacetylating a number of substrates including pro-apoptotic protein p53. The molecular mechanism by which DNA-damage activates SIRT1 is not known. By screening a kinase inhibitor library, we identified CK2 as a SIRT1 kinase. CK2 is a pleiotropic kinase with more than 300 substrates and well-known anti-apoptotic and pro-growth activities. We find that CK2 is recruited to SIRT1 after ionizing radiation (IR) and phosphorylates conserved residues Ser 154, 649, 651 and 683 in the N- and C-terminal domains of mouse SIRT1. Phosphorylation of SIRT1 increases its deacetylation rate but not if the four Ser residues are mutated. In addition, phosphorylation of SIRT1 increases its substrate-binding affinity. CK2-mediated phosphorylation increases the ability of SIRT1 to deacetylate p53 and protect cells from apoptosis after DNA damage. Based on these findings, we propose that CK2 protects against IR-induced apoptosis partly by phosphorylating and activating SIRT1. Thus, this work suggests that SIRT1 is a component of the expansive anti-apoptotic network controlled by CK2. Since expression of both CK2 and SIRT1 is upregulated with tumorigenesis and downregulated with senescence, the CK2-SIRT1 link sheds new light on how CK2 may regulate cancer development and aging

The Prognostic Implications of Cystic Change in Clear Cell Renal Cell Carcinoma

Background : Cystic renal cell carcinoma has been reported to have a good prognosis. However, previous studies included cases of multilocular cystic renal cell carcinoma, which has an excellent prognosis, and renal cell carcinoma with cystic necrosis, which has an adverse prognosis. Therefore, we analyzed the prognostic influence of cystic change in clear cell renal cell carcinoma after excluding those morphological features. Methods : We identified 225 patients with clear cell renal cell carcinoma who underwent nephrectomy between 2001 and 2003. The clinicopathologic features were compared with clinical outcomes. Results : Cystic change in clear cell renal cell carcinoma (n = 66) was significantly associated with younger patient age (< 55), smaller tumor size (<= 4 cm), lower pT stage (pT1, T2), M0 stage at initial diagnosis, lower tumor, node, and metastasis stage (I, II), and lower nuclear grade (1, 2). Patients with cystic change in clear cell renal cell carcinoma had significantly longer cancer-specific (p = 0.015) and progression-free survival (p = 0.004) than those without cystic change, by univariate analysis. Multivariate analysis revealed that cystic change significantly decreased the risk of cancer progression (risk ratio, 0.27; 95% confidence interval, 0.11 to 0.69). Conclusions : In patients with clear cell renal cell carcinoma, cystic change is a good independent predictor for survival.This work was supported by grant No. 04-2009-007 from the SNUH Research Fund.Jemal A, 2009, CA-CANCER J CLIN, V59, P225, DOI 10.3322/caac.20006Lopez-Beltran A, 2009, INT J UROL, V16, P432, DOI 10.1111/j.1442-2042.2009.02302.xGobbo S, 2008, AM J SURG PATHOL, V32, P1239Gong K, 2008, J CANCER RES CLIN, V134, P433, DOI 10.1007/s00432-007-0302-1Webster WS, 2007, UROLOGY, V70, P900, DOI 10.1016/j.urology.2007.05.029Lopez-Beltran A, 2006, EUR UROL, V49, P798, DOI 10.1016/j.eururo.2005.11.035Suzigan S, 2006, AM J CLIN PATHOL, V125, P217, DOI 10.1039/AH6FC77PYR2V6YAYFrank I, 2005, J UROLOGY, V173, P1889, DOI 10.1097/01.ju.0000158043.94525.d6Patard JJ, 2005, J CLIN ONCOL, V23, P2763, DOI 10.1200/JCO.2005.07.055Kim H, 2004, HUM PATHOL, V35, P1556, DOI 10.1016/j.humpath.2004.06.011Ficarra V, 2004, EUR UROL, V46, P559, DOI 10.1016/j.eururo.2004.07.002Han KR, 2004, UROL ONCOL-SEMIN ORI, V22, P410, DOI 10.1016/S1078-1439(03)00173-XImura J, 2004, APMIS, V112, P183Cheville JC, 2003, AM J SURG PATHOL, V27, P612Frank I, 2002, J UROLOGY, V168, P2395, DOI 10.1097/01.ju.0000035885.91935.d5Nassir A, 2002, UROLOGY, V60, P421GREENE FL, 2002, AJCC CANC STAGING MACorica FA, 1999, J UROLOGY, V161, P408Bielsa O, 1998, BRIT J UROL, V82, P16USUBUTUN A, 1998, INT UROL NEPHROL, V30, P391LYNCH CF, 1995, CANCER, V75, P316HARTMAN DS, 1986, UROLOGY, V28, P145

Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia

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