ABSTRACT
PURPOSE: To investigate the mRNA expression of B-MYB and MDM2 together with their p53 relatedness in clear cell renal cell carcinoma (ccRCC). METHODS: Genes were screened for their mRNA expression from 529 patients in a publicly available ccRCC cohort (TCGA). A cohort of 101 patients with ccRCC served as validation by qRT-PCR mRNA tissue expression analysis. RESULTS: Expression: B-MYB expression was significantly higher in high-grade tumours (p < 0.0001 and p = 0.048) and in advanced stages (p = 0.005 and p = 0.037) in both cohorts. Correlation: p53-B-MYB as well as MDM2-B-MYB showed significant correlations in local and low-grade ccRCCs, but not in high grade tumours or advanced stages (r < 0.3 and/or p > 0.05). Survival: Multivariable Cox regression of the TCGA cohort revealed B-MYB upregulation and low MDM2 expression as predictors for an impaired overall survival (OS) (HR 1.97; p = 0.0003; HR 2.94, p < 0.0001) and progression-free survival (PFS) (HR 2.86; p = 0.0005; HR 1.58, p = 0.046). In the validation cohort, the results were confirmed for OS by univariable, but not multivariable regression: high B-MYB expression (HR = 3.05, p = 0.035) and low MDM2 expression (HR 3.81, p value 0.036). CONCLUSION: In ccRCC patients with high-grade tumours and advanced stages, high B-MYB expression is common and is associated with poorer OS and PFS. These patients show a loss of their physiological B-MYB-p53 network correlation, suggesting an additional, alternative regulatory, oncogenic mechanism. Assuming further characterization of its signalling pathways, B-MYB could be a potential therapy target for ccRCC.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/pathology , Cell Cycle Proteins/metabolism , Gene Expression Regulation, Neoplastic , Kidney Neoplasms/pathology , Trans-Activators/metabolism , Tumor Suppressor Protein p53/metabolism , Aged , Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Cell Cycle Proteins/genetics , Disease Progression , Female , Follow-Up Studies , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Male , Middle Aged , Prognosis , Survival Rate , Trans-Activators/genetics , Tumor Suppressor Protein p53/geneticsABSTRACT
Nuclei of Saccharomyces cerevisiae cells contain a protein kinase, the activity of which is drastically reduced in response to an activation of the mating signal pathway by pheromone. Inhibition of this pheromone-sensitive kinase is also observed under conditions of constitutive activation of the signal pathway in a temperature-sensitive cdc70 mutant. The enzyme, which by SDS-PAGE has a molecular mass of 34,500 Da, is a protein serine kinase that phosphorylates several endogenous substrates in nuclear extracts. The activity of this kinase is temperature-resistant in a temperature-sensitive cdc28 mutant, indicating that it is not identical to p34CDC28, the catalytic component of the cell cycle protein kinase complex.
