Altered expression of the suppressors PML and p53 in glioblastoma cells with the antisense-EGF-receptor

Gene amplification and enhanced expression of the epidermal growth factor r eceptor (EGFR) represent the major molecular genetic alteration in glioblas tomas and it may play an essential role in cell growth and in the carcinoge nic process. On the other hand, the nuclear suppressor proteins PML and p53 are also known to play critical roles in cancer development and in suppres sing cell growth. Here we report that, in glioblastoma cells with defective EGFR function, the expressions of both promyelocytic leukaemia (PML) and p 53 were altered. Cells that were transfected with the antisense-cDNA of EGF R were found to have more cells in G1 and fewer cells in S phase. In additi on, the transfected cells were found to be non-responsive to EGF-induced ce ll growth. Interestingly, the expression of the suppressors p53 and PML wer e found to be significantly increased by immunohistochemical assay in the a ntisense-EGFR cells. Moreover, the PML expression in many of the cells was converted from the nuclear dot pattern into fine-granulated staining patter n. in contrast, the expressions of other cell cycle regulated genes and pro to-oncogene, including the cyclin-dependent kinase 4 (cdk4), retinoblastoma , p16(INK4a) and p21(H-ras), were not altered. These data indicate that the re are specific inductions of PML and p53 proteins which may account for th e increase in G1 and growth arrest in antisense-EGFR treated cells. It also indicates that the EGF, p53 and PML transduction pathways were linked and they may constitute an integral part of an altered growth regulatory progra mme. The interactions and cross-talks of these critical molecules may be ve ry important in regulating cell growth, differentiation and cellular respon se to treatment in glioblastomas. (C) 1999 Cancer Research Campaign.