p53 functions as a transcription factor involved in cell-cycle control, DNA repair, apoptosis and cellular stress responses. However, besides inducing cell growth arrest and apoptosis, p53 activation also modulates cellular senescence and organismal aging. Senescence is an irreversible cell-cycle arrest that has a crucial role both in aging and as a robust physiological antitumor response, which counteracts oncogenic insults. Therefore, via the regulation of senescence, p53 contributes to tumor growth suppression, in a manner strictly dependent by its expression and cellular context. In this review, we focus on the recent advances on the contribution of p53 to cellular senescence and its implication for cancer therapy, and we will discuss p53's impact on animal lifespan. Moreover, we describe p53-mediated regulation of several physiological pathways that could mediate its role in both senescence and aging.
p63 inhibits metastasis. Here, we show that p63 (both TAp63 and ΔNp63 isoforms) regulates expression of miR-205 in prostate cancer (PCa) cells, and miR-205 is essential for the inhibitory effects of p63 on markers of epithelial-mesenchymal transition (EMT), such as ZEB1 and vimentin. Correspondingly, the inhibitory effect of p63 on EMT markers and cell migration is reverted by anti-miR-205. p53 mutants inhibit expression of both p63 and miR-205, and the cell migration, in a cell line expressing endogenous mutated p53, can be abrogated by pre-miR-205 or silencing of mutated p53. In accordance with this in vitro data, ΔNp63 or miR-205 significantly inhibits the incidence of lung metastasis in vivo in a mouse tail vein model. Similarly, one or both components of the p63/miR-205 axis were absent in metastases or colonized lymph nodes in a set of 218 human prostate cancer samples. This was confirmed in an independent clinical data set of 281 patients. Loss of this axis was associated with higher Gleason scores, an increased likelihood of metastatic and infiltration events, and worse prognosis. These data suggest that p63/miR-205 may be a useful clinical predictor of metastatic behavior in prostate cancer
The p53 family member TAp73 is a transcription factor that plays a key role in many biological processes, including neuronal development. In particular, we have shown that p73 drives the expression of miR-34a, but not miR-34b and c, in mouse cortical neurons. miR-34a in turn modulates the expression of synaptic targets including synaptotagmin-1 and syntaxin-1A. Here we show that this axis is retained in mouse ES cells committed to differentiate toward a neurological phenotype. Moreover, overexpression of miR-34a alters hippocampal spinal morphology, and results in electrophysiological changes consistent with a reduction in spinal function. Therefore, the TAp73/miR-34a axis has functional relevance in primary neurons. These data reinforce a role for miR-34a in neuronal development.cell death | synaptogenesis | neuronal differentiation | hippocampus M icro-RNAs (miRs) are one family of a number of small noncoding regulatory RNAs (1). They are initially transcribed as pri-miRs, which are processed by a nuclear RNase III enzyme to form stem-loop structured premiRs. The premiRs are transported to the cytosol, where another RNase III cleaves off double-stranded portions of the hairpin to generate a short-lived dsRNA of approximately 20 to 25 nt. This duplex becomes unwound, and one strand (forming the mature miR) becomes incorporated into miR-protein complexes. The mature miR within the miR-protein complex recognizes complementary sites in the 3′ UTR of target genes, resulting in translational inhibition or destabilization of the target mRNAs and down-regulation of the encoded protein. During development, a number of miRs show distinct expression patterns during maturation of the CNS (2). For example, microarray miR profiling of embryonic, early postnatal, and adult brain revealed differential changes in nine miRNAs, including miR-9 and -124, and the levels of both these miRs increase markedly during the transition from neuronal precursors to mature neurons. miR-124 has also been implicated in the differentiation of neuroblastoma cells induced by retinoic acid (3).p73 is a member of the p53 family. Two distinct promoters transcribe different isoforms containing-TAp73-or lackingΔNp73-the aminoterminal transactivation domain (4); furthermore, extensive alternative 3′-splicing produces additional isoforms (5, 6). Trp73-KO mice have significant developmental abnormalities of the central nervous system, including congenital hydrocephalus, hippocampal dysgenesis, and defects of pheromone detection (7). Isoform-selective KOs have shown both a distinct neuronal phenotype and altered tumor susceptibility (8, 9). p53 can regulate several miRs (10). Indeed, the miR-34 family (miR-34a-c) is a p53 target (11-13), which can mimic several p53 effects in a cell type-specific manner. miR-34a is ubiquitous with the highest expression in mouse brain, and overexpression of miR-34a in neuroblastoma cell lines modulates neuronal-specific genes (14), whereas miR-34b and c are mainly expressed in the lung (15). Less information is available ...
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