第四章癌变机制.pptVIP

3. 肿瘤抑制基因举例： (1). RB基因：13q1.4，ESD含100%, 50%, 0％，4.5Kb mRNA 1) 1987年，250Kb, 27个外显子, p105磷酸化，只限于RB瘤 2) 基因产物：Leu拉链结构, 与DNA结合有关，每7个氨基酸有一个Leu，（α螺旋, 3.5个氨基酸一圈），一边亲水一边疏水(有Leu一侧)此侧可配对, 上游5’碱性区域与DNA结合。阻止基因转录。 3) 主要功能及机制, 参与细胞周期调控 A. RB随细胞周期其磷酸化程度改变 B. 病毒感染 (DNA) HPV-16E7 磷酸化变化小, 有复合物存在 Ad E1A SVLT 非磷酸化物+转化蛋白→抑制消失 Figure 5.2 Mechanisms causing inactivation of the second RB1 allele (1) Loss of chromosome 13 carrying the intact allele; (2) Deletion; (3) Independent mutation; (4) Recombination; (5) Promoter hypermethylation. Mechanisms (1), (2), and (4) are associated with LOH. cf. also Figure 2.8. The mutated first allele is marked by a lightning. White glow or glint in one or both eyes Have white pupils in pictures Has crossed or misaligned eyes (2). P53基因 有广普性特征, 点突变----oncogene 1)主要特点: 17号染色体, 16--20Kb, 11个外显子(exon)。 mRNA, 2.5Kb, 393个Aa。 核内信号证明核内作用，与DNA结合4个P53区域为酸性与组蛋白作用。 2) 肿瘤中异常 点突变 (1) 多为错义突变(碱基互换) (2) 130--290 Aa 有4个易突变区域 (3) 175, 196, 213, 248, 273, 282, 易突变位点 (4) 突变频率因组织而异 (5) 肺癌中G→T, 其它G→A (6) 散发 P53突变仅在肿瘤细胞中 遗传, 单个基因突变后遗传, P53在体细胞中都有 3) 功能机制: 生长负调节作用 Figure 5.5 Structure and functional domains of TP53 A: Organization of the gene. The introns are not fully to scale. The grey bar marks the exons encoding the basic DNA-binding domain. B: Features of the protein. C-ter: C-terminal interaction domain; NES/NLS nuclear export/localization signal; PXXP: proline-rich domain. Figure 5.6 A sketch of the TP53 network Viral oncogenes and p53 network (Nature 408:306, 2000) Figure 5.7 Posttranslational regulation of TP53 Note that only the N-terminal and C-terminal domains of the protein are shown. Most modifications are phosphorylations except at Lys320 and 373 (acetylation) and 386 (sumolation). The modif