Apoptosis inhibitor as a suppressor of tumor progression: expression of Bcl-2 eliminates selective advantages for p53-deficient cells in the tumor.
Inactivation of p53 and expression of Bcl-2, frequently occurring during tumor progression, have different prognostic value: while inactivation of p53 is generally associated with unfavorable prognosis, expression of Bcl-2 often correlates with better clinical outcome and delays selection of metastatic variants of experimental tumors. To analyze the mechanisms underlying the "anti-progression" function of Bcl-2, we engineered tumor cell variants differing in their p53 status and Bcl-2 expression and compared their expansion in experimental tumors. Although neither p53 suppression nor Bcl-2-expression altered cell growth properties in vitro, both variants showed rapid accumulation in growing tumors in vivo, presumably due to their resistance to hypoxia. However, no expansion of p53-deficient variants occurred in the tumors formed by Bcl-2-overexpressing cells, indicating that p53 deficiency has no selective advantages in the Bcl-2-expressing environment. Importantly, expression of Bcl-2, unlike p53 suppression, did not lead to genomic instability as judged by the frequencies of gene amplification. Thus, acquisition of Bcl-2 expression is as advantageous for tumor cell growth in vivo as is p53 inactivation but does not affect genomic stability and creates the environment restrictive for the expansion of genetically unstable and potentially malignant p53-deficient cells, causing a delay in tumor progression and explaining the different prognostic value of Bcl-2 and p53.
Gurova
Katerina V
KV
Department of Molecular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Kwek
Serena S S
SS
Koman
Igor E
IE
Komarov
Andrei P
AP
Kandel
Eugene
E
Nikiforov
Mikhail A
MA
Gudkov
Andrei V
AV
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002455:Cell Division; D002461:Cell Line, Transformed / Q000187:drug effects / Q000473:pathology; D006224:Cricetinae; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D017930:Genes, Reporter; D019254:Genes, bcl-2; D016158:Genes, p53; D006801:Humans; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012641:Selection, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000502:physiology
D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53