We have previously reported that the 3p21 tumor suppressor BLU regulates cell cycle by blocking JNK/MAPK signaling. Another member of the MAPK family, extracellular signal response kinase (ERK), is induced by the RAS-RAF-MEK-ERK pathway and is targeted in anticancer therapy. The effects of BLU on tumor growth were evaluated by measuring the size of nasopharyngeal carcinoma (NPC) xenografted tumors intra-tumorally injected with BLU adenovirus 5 (BLU Ad5) and the viability of NPC cells transferred with BLU. Tumor size was correlated with downregulation of the ERK pathway by BLU. Phosphorylation of ERK and Elk reporter activities were assayed. The regulated cyclins D1 and B1 were measured by CCND1 and CCNB1 gene promoter activity by co-transfection of BLU, RAS V12G, together with BLU+RAS V12G, pCD316+RAS V12G. The cell cycle phase distribution was determined by FACS-based DNA content assay. The data showed that growth of the xenografted tumor was inhibited and viability of HONE-1 cells was reduced by recombinant BLU. BLU down-regulated ERK signaling by reducing protein substrate phosphorylation, inhibiting Elk reporter activity, and blocking promoter activities of the CCND1 gene and reduced cyclins D1 expression to arrest the cell cycle at the G1 phase. The population of G2/M cells was also remarkably decreased. HRAS V12G activated ERK and cyclin D1 and B1 promoters, and the effects were antagonized by BLU. Taken together, our results suggested that BLU inhibited ERK signaling, downregulated cyclins D1 and B1, and prevented cell cycle progression through interfering with HRAS V12G signaling to exert tumor suppression.
Keywords: BLU/ZMYND10; H-RAS; MAPK/ERK; cell cycle; cyclin B1; cyclin D1.
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