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. Here, we show that p73 drives the expression of microRNA (miR)-34a, but not miR-34b and -c, by acting on specific binding sites on the miR-34a promoter. Expression of miR-34a is modulated in parallel with that of TAp73 during in vitro differentiation of neuroblastoma cells and cortical neurons. Retinoid-driven neuroblastoma differentiation is inhibited by knockdown of either p73 or miR-34a. Transcript expression of miR-34a is significantly reduced in vivo both in the cortex and hippocampus of p73 −/− mice; miR-34a and TAp73 expression also increase during postnatal development of the brain and cerebellum when synaptogenesis occurs. Accordingly, overexpression or silencing of miR-34a inversely modulates expression of synaptic targets, including synaptotagmin-1 and syntaxin-1A. Notably, the axis TAp73/miR-34a/synaptotagmin-1 is conserved in brains from Alzheimer's patients. These data reinforce a role for TAp73 in neuronal development.cell death | neurodegeneration | Alzheimer disease T he p53-family member Trp73 is transcribed from two distinct promoters, resulting in isoforms containing or lacking the Nterminal TA domain, known as TAp73 (1, 2) and ΔNp73 (3), respectively; additionally, alternative 3′-splicing produces further variants (α, β, and so forth). In keeping with their sequence and structural similarities, TAp73 can mimic several p53 functions, including the transactivation of p21, Puma, and Bax, although p73 also has distinct transcriptional targets. Indeed, p73 −/− mice show developmental defects of the CNS; for example, congenital hydrocephalus, hippocampal dysgenesis, and defects of pheromone detection rather than the enhanced tumor susceptibility of p53 −/− mice (4). This development is not simply because of apoptosis, as the ectopic expression of p73 induces neurite outgrowth and expression of neuronal markers in neuroblastoma cell lines (5) and in primary oligodendrocytes (6).Several microRNAs (miRs) are regulated by p53 (7), although p73-dependent miRs have been less well studied. In particular, the miR-34 family (miR-34a to -c) has been shown to be a direct target of p53 (8-10). Ectopic expression of miR-34 mimics several p53 effects, although in a cell type-specific manner. In mice, miR-34a is ubiquitous with the highest expression in brain, and overexpression of miR-34a in neuroblastoma cell lines modulates neuronal-specific genes (11); miR-34b and -c are mainly in the lung (12).Because both p73 and miRs, including miR-34a, have been implicated in neuronal differentiation, we have investigated the possibility that p73 drives miR-34a expression using WT and p73-null mice. We demonstrate that miR-34a is transcriptionally regulated by TAp73 and that, in turn, miR-34a regulates the expression of a number of synaptic proteins, in particular synaptotagmin I and syntaxin 1A in cortical neurons. Moreover, neuronal architecture is disorganized in p73-null mice, and manipulation of miR-34a expressi...

p73 is a tumor suppressor belonging to the p53 family of transcription factors. Distinct isoforms are transcribed from the p73 locus. The use of 2 promoters at the N-terminus allows the expression of an isoform containing (TAp73) or not containing (ΔNp73) a complete N-terminal transactivation domain, with the latter isoform capable of a dominant negative effect over the former. In addition, both N-terminal variants are alternatively spliced at the C-terminus. TAp73 is a bona fide tumor suppressor, being able to induce cell death and cell cycle arrest; conversely, ΔNp73 shows oncogenic properties, inhibiting TAp73 and p53 functions. Here, we discuss the latest findings linking p73 to cancer. The generation of isoform specific null mice has helped in dissecting the contribution of TA versus ΔNp73 isoforms to tumorigenesis. The activity of both isoforms is regulated transcriptionally and by posttranslational modification. p73 dysfunction, particularly of TAp73, has been associated with mitotic abnormalities, which may lead to polyploidy and aneuploidy and thus contribute to tumorigenesis. Although p73 is only rarely mutated in cancer, the tumor suppressor actions of TAp73 are inhibited by mutant p53, a finding that has important implications for cancer therapy. Finally, we discuss the expression and role of p73 isoforms in human cancer, with a particular emphasis on the neuroblastoma cancer model. Broadly, the data support the hypothesis that the ratio between TAp73 and ΔNp73 is crucial for tumor progression and therapeutic response.

The epidermis, the outer layer of the skin composed of keratinocytes, develops following the action of the transcription factor p63. The mouse Trp63 gene contains two promoters, driving the production of distinct proteins, one with an N-terminal trans-activation domain (TAp63) and one without (ΔNp63), although their relative contribution to epidermal development is not clearly established. To identify the relative role of p63 isoforms in relation to IKKα, also known to be essential for epithelial development, we performed both molecular and in vivo analyses using genetic complementation in mice. We found that the action of TAp63 is mediated at the molecular level by direct and indirect transactivation of IKKα and Ets-1, respectively. We also found that ΔNp63 upregulates IKKα indirectly, through GATA-3. Our data are consistent with a role for p63 directly upstream of IKKα in epithelial development.