INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53
INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53
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DOI：
10.1101/gad.13.20.2670
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发表时间：
1999-10-15
影响因子：
10.5
通讯作者：
Lowe, SW
中科院分区：
文献类型：
--
作者：
Schmitt, CA;McCurrach, ME;Lowe, SW
INK4a/ARF基因座编码视网膜母细胞瘤和p53抑癌基因产物的上游调控因子。为了比较这些基因座对肿瘤发展和治疗反应的影响，使用E-u-myc转基因淋巴瘤模型来产生带有INK4a/ARF Rb或p53基因突变的基因定义的肿瘤。与p53基因缺失的淋巴瘤一样，INK4a/ARF基因缺失的淋巴瘤形成迅速，侵袭性强，存在细胞凋亡缺陷，在体内外对化疗具有明显的耐药性。此外，NK4a/ARF(-/-)淋巴瘤显示P53活性降低，尽管存在野生型P53基因。因此，INK4a/ARF和P53突变通过破坏重叠的肿瘤抑制功能而导致侵袭性肿瘤。这些数据对于理解人类肿瘤的临床行为具有重要意义。
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 E mu-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, NK4a/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.