TP53 loss of function - with associated dominant-negative effects - is the main mechanism that will impair TP53 tumor suppressive function, regardless of whether a neomorphic phenotype is associated with some of these variants.doi:10.1038/s41418-024-01391-6Andreas C. Joerger...
①功能丧失(loss of function,LOF),即突变型 p53 蛋白丧失了p53 正常功能; ②显性负效应(dominant negative effect,DNE),即突变型p53 蛋白干扰细胞内野生型p53的正常功能; ③功能获得(gain of function,GOF),突变型p53获得了野生型p53缺失时未观察到的额外活性,如与肿瘤抑制因子p63或p73共同聚集,增强细胞转移等。
Copy number loss on 17p was also significantly higher among the lowest MD quintile cancers when analysis was restricted to luminal cancers of ductal histology (Fig. 2c). Nine out of the ten cases with 17p LOH carried a TP53 mutation. The mean homologous recombination deficiency (HRD) sum ...
While loss-of-function events in TP53 are very common in cancer, the R273 variants seem not only to result in loss of tumor-suppression, but also act as a gain-of-function mutation that can promote tumorigenesis in mouse models. This mutant is also more responsive to treatment with ...
These results are consistent with previous studies showing that cancer cells harboring the TP53 loss-of-function mutation have a dysfunctional G1/S checkpoint and primarily rely on the G2/M checkpoint to arrest the cell cycle and execute DNA repair.53,54 That TP53-deficient cells depend on ATM...
[85]. BecauseTP53mutation typically results in loss of function, it has been difficult to identify methods for targeting mutant p53[86]. Furthermore, several different mutations of p53 have been identified, and different mutations can result in different effects in human cancers, thus a single ...
转录因子基因TP53是人类癌症中突变频率最高的抑癌基因,其中80%的突变均为聚集在DNA结合区域的可改变编码蛋白序列的错义突变(missense mutation)。研究发现,在肿瘤克隆进化过程中,TP53的杂合性丢失(loss of heterozygosity)并不是必要的;这一特殊突变模式...
In “loss-of-function,” p53 does not maintain its tumor-suppressor function. “Dominant-negative” is represented by wild-type p53 inhibition by mutated p53 protein (originating from one mutant allele). In “gain-of-function,” p53 behaves similar to an oncogene [6]. The type of genetic ...
Somatic loss-of-function mutations in the gene encoding tumor suppressor protein p53 (TP53) are frequently observed in various cancers. However, numerous studies suggest that TP53 regulates malignant phenotypes by gain-of-function (GOF) mutations. Here we demonstrate that a TP53 GOF mutation promotes...
Classifying TP53 status in human cancer as ‘inactivated’ or ‘loss-of-function’ is misleading. Many mutant p53 variants are oncogenic with multiple GOF activities essential for neoplastic transformation. Open Questions How does the diversity of oncogenic p53 variants contribute to the heterogeneity o...