Freije Ana, Molinuevo Rut, Ceballos Laura, Cagigas Marta, Alonso-Lecue Pilar, Rodriguez René, Menendez Pablo, Aberdam Daniel, De Diego Ernesto, Gandarillas Alberto
Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, Spain.
Lab 2-ORL, Instituto Universitario de Oncología de Asturias (IUOPA) Hospital Universitario Central de Asturias (HUCA), Oviedo 33006, Spain.
Cell Rep. 2014 Nov 20;9(4):1349-60. doi: 10.1016/j.celrep.2014.10.012. Epub 2014 Nov 6.
Tumor suppressor p53 is a major cellular guardian of genome integrity, and its inactivation is the most frequent genetic alteration in cancer, rising up to 80% in squamous cell carcinoma (SCC). By adapting the small hairpin RNA (shRNA) technology, we inactivated endogenous p53 in primary epithelial cells from the epidermis of human skin. We show that either loss of endogenous p53 or overexpression of a temperature-sensitive dominant-negative conformation triggers a self-protective differentiation response, resulting in cell stratification and expulsion. These effects follow DNA damage and exit from mitosis without cell division. p53 preserves the proliferative potential of the stem cell compartment and limits the power of proto-oncogene MYC to drive cell cycle stress and differentiation. The results provide insight into the role of p53 in self-renewal homeostasis and help explain why p53 mutations do not initiate skin cancer but increase the likelihood that cancer cells will appear.
肿瘤抑制因子p53是基因组完整性的主要细胞守护者，其失活是癌症中最常见的基因改变，在鳞状细胞癌（SCC）中高达80%。通过采用小发夹RNA（shRNA）技术，我们使源自人类皮肤表皮的原代表皮细胞中的内源性p53失活。我们表明，内源性p53的缺失或温度敏感型显性负构象的过表达都会触发自我保护的分化反应，导致细胞分层和排出。这些效应在DNA损伤后出现，并在不进行细胞分裂的情况下退出有丝分裂。p53保留了干细胞区室的增殖潜力，并限制了原癌基因MYC驱动细胞周期应激和分化的能力。这些结果为p53在自我更新稳态中的作用提供了见解，并有助于解释为什么p53突变不会引发皮肤癌，但会增加癌细胞出现的可能性。
