PDF(Pubmed)
Abstract：
The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations in the TP53 gene, which not only abrogate the tumor-suppressive functions but also confer p53 mutant proteins with oncogenic potential. The latter is achieved through so-called gain-of-function (GOF) mutations that promote cancer progression, metastasis, and therapy resistance by deregulating transcriptional networks, signaling pathways, metabolism, immune surveillance, and cellular compositions of the microenvironment. Despite recent progress in understanding the complexity of mutp53 in neoplastic development, the exact mechanisms of how mutp53 contributes to cancer development and how they escape proteasomal and lysosomal degradation remain only partially understood. In this review, we address recent findings in the field of oncogenic functions of mutp53 specifically regarding, but not limited to, its implications in metabolic pathways, the secretome of cancer cells, the cancer microenvironment, and the regulating scenarios of the aberrant proteasomal degradation. By analyzing proteasomal and lysosomal protein degradation, as well as its connection with autophagy, we propose new therapeutical approaches that aim to destabilize mutp53 proteins and deactivate its oncogenic functions, thereby providing a fundamental basis for further investigation and rational treatment approaches for TP53-mutated cancers.
摘要：
p53蛋白是细胞完整性的主要调节因子,主要是由于其肿瘤抑制功能。大约一半的人类癌症携带TP53基因突变，它不仅废除了肿瘤抑制功能，而且赋予p53突变蛋白具有致癌潜力。后者是通过促进癌症进展的所谓的功能获得（GOF）突变来实现的。转移,和通过解除调节转录网络的治疗抗性，信号通路，新陈代谢，免疫监视,和微环境的细胞组成。尽管最近在了解mutp53在肿瘤发展中的复杂性方面取得了进展，关于mutp53如何促进癌症发展以及它们如何逃避蛋白酶体和溶酶体降解的确切机制,目前还只是部分了解.在这次审查中,我们讨论了mutp53致癌功能领域的最新发现，但不限于,它对代谢途径的影响，癌细胞的分泌体，癌症微环境，以及异常蛋白酶体降解的调节方案。通过分析蛋白酶体和溶酶体蛋白降解，以及它与自噬的联系，我们提出了新的治疗方法，旨在使mutp53蛋白不稳定并使其致癌功能失活，从而为TP53突变癌症的进一步研究和合理治疗方法提供了基础。
