Schmitt C A, McCurrach M E, de Stanchina E, Wallace-Brodeur R R, Lowe S W
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Genes Dev. 1999 Oct 15;13(20):2670-7. doi: 10.1101/gad.13.20.2670.
The INK4a/ARF locus encodes upstream regulators of the retinoblastoma and p53 tumor suppressor gene products. To compare the impact of these loci on tumor development and treatment response, the Emu-myc transgenic lymphoma model was used to generate genetically defined tumors with mutations in the INK4a/ARF, Rb, or p53 genes. Like p53 null lymphomas, INK4a/ARF null lymphomas formed rapidly, were highly invasive, displayed apoptotic defects, and were markedly resistant to chemotherapy in vitro and in vivo. Furthermore, INK4a/ARF(-/-) lymphomas displayed reduced p53 activity despite the presence of wild-type p53 genes. Consequently, INK4a/ARF and p53 mutations lead to aggressive tumors by disrupting overlapping tumor suppressor functions. These data have important implications for understanding the clinical behavior of human tumors.
INK4a/ARF基因座编码视网膜母细胞瘤和p53肿瘤抑制基因产物的上游调节因子。为了比较这些基因座对肿瘤发生和治疗反应的影响,采用Emu-myc转基因淋巴瘤模型来生成在INK4a/ARF、Rb或p53基因中存在突变的基因明确的肿瘤。与p53缺失的淋巴瘤一样,INK4a/ARF缺失的淋巴瘤形成迅速,具有高度侵袭性,表现出凋亡缺陷,并且在体外和体内对化疗均具有明显抗性。此外,尽管存在野生型p53基因,但INK4a/ARF(-/-)淋巴瘤的p53活性仍降低。因此,INK4a/ARF和p53突变通过破坏重叠的肿瘤抑制功能导致侵袭性肿瘤。这些数据对于理解人类肿瘤的临床行为具有重要意义。