Perez-Losada Jesus, Wu Di, DelRosario Reyno, Balmain Allan, Mao Jian-Hua
Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, CA 94143, USA.
Oncogene. 2005 Aug 18;24(35):5521-4. doi: 10.1038/sj.onc.1208799.
p53 is one of the most important tumor suppressor genes in human cancer, but the roles of its homologues p63 and p73 in tumor suppression, alone or in collaboration with p53, remains controversial. Both p63 and p73 can be deregulated after DNA damage, and induce cell cycle arrest and apoptosis, but mice carrying inactive alleles of these genes do not develop spontaneous tumors. Since heterozygous loss of p53 confers strong sensitization to radiation-induced lymphoma development, we investigated the possibility that radiation exposure may reveal previously undetected tumor suppressor properties in p63 or p73, alone or in combination with p53. Animals heterozygous for p63 or p73, as well as both double heterozygous p53/p63 or p53/p73 mice, showed no significant differences in tumor latency, spectrum or frequency after gamma-radiation, compared to their control counterparts. Deletions were found near the p63 locus on chromosome 16 in radiation-induced tumors, but these frequently included the knockout allele. No deletions or LOH involving the p73 gene were detected, and expression of both genes was maintained in the tumors. We conclude that p53 homologues do not contribute to p53 tumor suppressor activity in lymphoma development.
p53是人类癌症中最重要的肿瘤抑制基因之一，但其同源物p63和p73在单独或与p53协同发挥肿瘤抑制作用方面，仍存在争议。DNA损伤后，p63和p73均可发生失调，并诱导细胞周期停滞和凋亡，但携带这些基因无活性等位基因的小鼠不会自发发生肿瘤。由于p53杂合性缺失会使小鼠对辐射诱导的淋巴瘤发生产生强烈的敏感性，因此我们研究了辐射暴露是否可能揭示p63或p73单独或与p53联合时先前未被检测到的肿瘤抑制特性。与对照小鼠相比，p63或p73杂合的动物，以及p53/p63或p53/p73双杂合小鼠在接受γ射线辐射后，肿瘤潜伏期、谱型或发生率均无显著差异。在辐射诱导的肿瘤中，发现16号染色体上p63基因座附近存在缺失，但这些缺失常常包含敲除等位基因。未检测到涉及p73基因的缺失或杂合性丢失，且这两个基因在肿瘤中均维持表达。我们得出结论，在淋巴瘤发生过程中，p53同源物对p53的肿瘤抑制活性没有贡献。
