Olivos David J, Mayo Lindsey D
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Int J Mol Sci. 2016 Nov 26;17(12):1982. doi: 10.3390/ijms17121982.
Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution of p53 detailing the significant discoveries of each decade since its first report in 1979. In this review, we will highlight the emerging non-canonical functions and regulation of p53 in stem cells. We will focus on general themes shared among p53's functions in non-malignant stem cells and cancer stem-like cells (CSCs) and the influence of p53 on the microenvironment and CSC niche. We will also examine p53 gain of function (GOF) roles in stemness. Mutant p53 (p53) GOFs that lead to survival, drug resistance and colonization are reviewed in the context of the acquisition of advantageous transformation processes, such as differentiation and dedifferentiation, epithelial-to-mesenchymal transition (EMT) and stem cell senescence and quiescence. Finally, we will conclude with therapeutic strategies that restore wild-type p53 (p53) function in cancer and CSCs, including RING finger E3 ligases and CSC maintenance. The mechanisms by which p53 and p53 influence stemness in non-malignant stem cells and CSCs or tumor-initiating cells (TICs) are poorly understood thus far. Further elucidation of p53's effects on stemness could lead to novel therapeutic strategies in cancer research.
自近40年前被发现以来，p53已成为不同研究领域中被研究的基因和蛋白质的前沿热点，并且因其作为肿瘤抑制因子在癌症中的作用而最为人所熟知。莱文和奥伦（2009年）回顾了p53的演变，详述了自1979年首次报道以来每个十年的重大发现。在本综述中，我们将重点介绍p53在干细胞中新兴的非经典功能和调控机制。我们将聚焦于p53在非恶性干细胞和癌症干细胞样细胞（CSCs）中的功能所共有的一般主题，以及p53对微环境和CSC生态位的影响。我们还将研究p53在干性方面的功能获得（GOF）作用。在获得有利的转化过程，如分化和去分化、上皮-间质转化（EMT）以及干细胞衰老和静止的背景下，对导致存活、耐药和定植的突变型p53（p53）GOF进行了综述。最后，我们将总结在癌症和CSCs中恢复野生型p53（p53）功能的治疗策略，包括泛素连接酶E3连接酶和CSC维持。到目前为止，p53和p53影响非恶性干细胞和CSCs或肿瘤起始细胞（TICs）干性的机制尚不清楚。进一步阐明p53对干性的影响可能会为癌症研究带来新的治疗策略。
