Alterations of the p15, p16, and p18 genes in osteosarcoma
Alterations of the p15, p16, and p18 genes in osteosarcoma
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DOI：
10.1016/0165-4608(95)00216-2
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发表时间：
1996-02-01
影响因子：
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通讯作者：
Koeffler, HP
中科院分区：
文献类型：
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作者：
Miller, CW;Aslo, A;Koeffler, HP
细胞周期蛋白依赖的蛋白激酶(CDK)通过与细胞周期蛋白的相互作用调节细胞周期检查点的进程。这一过程被CDK抑制剂(CDK)所平衡，CDK抑制剂可以抑制细胞周期的进展。由于CDKI的表达抑制了细胞的增殖，CDK1可能具有肿瘤抑制的作用。一类CDKI具有至少四个成员(p15(INK4B)、p16(INK4)、p18和p19)。其中两个基因p15(INK4B)和p16(INK4)已被定位到染色体9p21，这是一种在各种癌症中经常丢失的区域。P16(INK4)在多种肿瘤和细胞系中均有表达。我们分析了52例骨肉瘤(包括11例外植体)和23例其他类型肉瘤中p15(INK4B)、p16(INK4)和p18的改变。这些CDKI基因编码区的单链构象多态分析[聚合酶链式反应-单链构象多态分析]在1例软组织肉瘤中发现了p16(INK4)外显子1的错义突变。Southern blotting检测到2例骨肉瘤和1例软组织肉瘤中p15(INK4B)和p16(INK4)基因完全缺失。在后一种情况下，用与INK4基因紧密连锁的微卫星探针观察到染色体9p21 TVA的杂合性丢失(LOH)。在8个骨肉瘤细胞系中有5个检测到p15(INK4B)和p16(INK4)基因的缺失。相比之下，在任何样本中都没有检测到p18的变化，这些数据表明，p15(INK4B)和p18(INK4)基因的变化，而不是p18，可能发生在类似于5%的肉瘤中。然而，p15(INK4B)和p16(INK4)基因的缺失在骨肉瘤细胞系中很常见，可能在培养的肿瘤细胞生长中起作用。值得注意的是，所有七个可检测到的缺失都涉及p15(INK4B)和p16(INK4)基因，这表明这两个基因都有助于单独的肿瘤抑制活性。
Activation of cyclin-dependent kinases (CDKs) by interaction with cyclins regulates progression through cell cycle checkpoints. This process is counterbalanced by CDK inhibitors (CDKls), which can inhibit progression through the cell cycle. Because CDKI expression acts to inhibit cellular proliferation, CDKls may have a role as tumor suppressors. One class of CDKIs, characterized by the presence of ankyrin repents, has at least four members(p15(INK4B), p16(INK4), p18, and p19). Two of these, p15(INK4B) and p16(INK4), have been mapped to chromosome 9p21, a region of frequent loss in a wide variety of cancers. Alterations of p16(INK4) have been detected in various tumors and cell lines. We analyzed p15(INK4B), p16(INK4) and p18 alterations in 52 osteosarcomas (including 11 explants), and 23 other various sarcomas. Single-stranded conformation polymorphism analysis [polymerase chain reaction (PCR-SSCP)] of the coding regions of these CDKI genes detected a missense mutation of p16(INK4) exon 1 in one soft tissue sarcoma. Southern blotting detected complete deletion of p15(INK4B) and p16(INK4) genes in osteosarcomas from 2 patients and a soft tissue sarcoma from another individual. Loss of heterozygosity (LOH) at chromosome 9p21 tvas observed with a microsatellite probe closely linked to the INK4 genes in the latter case. Deletions of both p15(INK4B) and p16(INK4) genes were detected in five of eight osteosarcoma cell lines. By contrast, no alterations of p18 were detected in any sample, Together these data suggest that alterations of the p15(INK4B) and p18(INK4) genes, but not p18, may occur in similar to 5% of sarcomas. However, deletions of the p15(INK4B) and p16(INK4) genes are frequent in osteosarcoma cell lines and probably have a role in tumor cell growth in culture. Notably, all seven detectable deletions involved both p15(INK4B) and p16(INK4) genes, suggesting that both contribute individual tumor suppressor activity.