Hairless regulates p53 target genes to exert tumor suppressive functions in glioblastoma

Glioblastoma (GBM) is the most common malignant brain tumor and is associated with a poor prognosis, with most patients living less than a year after diagnosis. Given that GBM nearly always recurs after conventional treatments, there is an urgent need to identify novel molecular targets. Hairless (HR) is a nuclear factor enriched in the skin and has been previously implicated in hair cycling. HR is also highly expressed in the brain, but its significance is unknown. We found that human hairless gene (HR) expression is significantly decreased in all GBM subtypes compared with normal brain tissue and is predictive of prognosis, which suggests that loss of HR expression can contribute to GBM pathogenesis. HR was recently discovered to bind to and regulate p53 responsive elements, and thus we hypothesized that HR may have a tumor suppressive function in GBM by modulating p53 target gene expression. We found that HR indeed regulates p53 target genes, including those implicated in cell cycle progression and apoptosis in the GBM-derived U87 cell line, and restoring HR expression triggered G2/M arrest and apoptosis. An analysis of sequenced genomes from patients with GBM revealed 10 HR somatic mutations in patients with glioma, two of which are located in the histone demethylase domain of HR. These two mutations, P996S and K1004N, were reconstructed and found to have impaired p53 transactivating properties. Collectively, the results of our study suggest that HR has tumor suppressive functions in GBM, which may be clinically relevant and a potential avenue for therapeutic intervention.     

Cellular and organismal ageing: Role of the p53 tumor suppressor protein in the induction of transient and terminal senescence

In recent years, an impact of the p53 tumor suppressor protein in the processes of cellular and organismal ageing became evident. First hints were found in model organisms like Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster where a clear connection between ageing phenotypes and pathways that are regulated by p53, were found. Interestingly, pathways that are central to the ageing process are usually also involved in energy metabolism and are highly conserved throughout evolution. This also supports the long known empiric finding that caloric restriction has a positive impact on the life span of a wide variety of organisms. Within the last years, on the molecular level, an involvement of the insulin-like growth factor and of the histone deacetylase SRIT1 could be shown. Insight on the impact of p53 on ageing at the organismal level came from mice expressing aberrant forms of the p53 protein. Obviously, the balance of the full length p53 protein and of the shorter p44/DeltaNp53 isomer bear a strong impact on ageing. The shorter isoform regulates full length p53 and in cases where there is too much of the longer isoform, this leads to elevated apoptosis resulting in decreased tumor incidence but also in premature ageing due to exhaustion of the renewal potential. Therefore, modulating the expression of the truncated p53 isoform accordingly, might lead to increased health-span and elevated life-span.     

Multiple domains of the mouse p19ARF tumor suppressor are involved in p53-independent apoptosis

The ARF (p19ARF for the mouse ARF consisting of 169 amino acids and p14ARF for the human ARF consisting of 132 amino acids) genes upregulate p53 activities to induce cell cycle arrest and sensitize cells to apoptosis by inhibiting Mdm2 activity. p53-independent apoptosis also is induced by ectopic expression of p19ARF. We constructed various deletion mutants of p19ARF with a cre/loxP-regulated adenoviral vector to determine the regions of p19ARF which are responsible for p53-independent apoptosis. Ectopic expression of the C-terminal region (named C40) of p19ARF whose primary sequence is unique to the rodent ARF induced prominent apoptosis in p53-deficient mouse embryo fibroblasts. Relatively low-grade but significant apoptosis also was induced in p53-deficient mouse embryo fibroblasts by ectopic expression of p19ARF1-129, a p19ARF deletion mutant deficient in the C40 region. In contrast, ectopic expression of the wild-type p14ARF did not induce significant apoptosis in human cells. Taken together, we concluded that p53-independent apoptosis was mediated through multiple regions of the mouse ARF including C40, and the ability of the ARF gene to mediate p53-independent apoptosis has been not well conserved during mammalian evolution.     

p53-independent apoptosis is induced by the p19ARF tumor suppressor

p19(ARF) is a potent tumor suppressor. By inactivating Mdm2, p19(ARF) upregulates p53 activities to induce cell cycle arrest and sensitize cells to apoptosis in the presence of collateral signals. It has also been demonstrated that cell cycle arrest is induced by overexpressed p19(ARF) in p53-deficient mouse embryonic fibroblasts, only in the absence of the Mdm2 gene. Here, we show that apoptosis can be induced without additional apoptosis signals by expression of p19(ARF) using an adenovirus-mediated expression system in p53-intact cell lines as well as p53-deficient cell lines. Also, in primary mouse embryonic fibroblasts (MEFs) lacking p53/ARF, p53-independent apoptosis is induced irrespective of Mdm2 status by expression of p19(ARF). In agreement, p19(ARF)-mediated apoptosis in U2OS cells, but not in Saos2 cells, was attenuated by coexpression of Mdm2. We thus conclude that there is a p53-independent pathway for p19(ARF)-induced apoptosis that is insensitive to inhibition by Mdm2.     

Cell-mediated cytotoxicity can be regulated by p53 tumor suppressor gene activity in vitro

Summary— The wild-type human p53 tumor suppressor gene was tested for its ability to modulate cytotoxic activity of in vitro activated peripheral blood lymphocytes. Peripheral blood mononuclear cells (PBMCs) were stimulated by phytohemagglutinin (PHA), interferon α2b (IFNα2b), interleukin 2 (IL-2) or their combinations to induce cytotoxicity. This stimulation significantly increased the percentage of cells expressing p53, which was at its maximum when induced by IL-2 combined with IFNα2b. The role of p53 in the modulation of different aspects of cytotoxic activity of these cells was analyzed by studying the effects of p53 abrogation by antisense oligonucleotide (p53 AS) treatment in comparison with p53 sense or scrambled (missense) oligonucleotide (p53 S or p53 MS) treatment. We show that p53 plays a key role through induction of apoptosis in target cells (tumor necrosis factor pathway) rather than through osmolytic degeneration (perforin pathway) which is only slightly increased by p53 abrogation. Meanwhile, in vitro abrogation of p53 expression in PBL was found to be accompanied by an increase of CD8+ lymphocytes and an important increase of the CD56 ‘bright’ NK cell sub-population.     

p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53

p53 mutations, occurring in two-thirds of all human cancers, confer a gain of function phenotype, including the ability to form metastasis, the determining feature in the prognosis of most human cancer. This effect seems mediated at least partially by its ability to physically interact with p63, thus affecting a cell invasion pathway, and accordingly, p63 is deregulated in human cancers. In addition, p63, as an 'epithelial organizer', directly impinges on epidermal mesenchimal transition, stemness, senescence, cell death and cell cycle arrest, all determinant in cancer, and thus p63 affects chemosensitivity and chemoresistance. This demonstrates an important role for p63 in cancer development and its progression, and the aim of this review is to set this new evidence that links p63 to metastasis within the context of the long conserved other functions of p63.     

The p53 tumor suppressor: Critical regulator of life & death in cancer

p53 is the most commonly mutated or deleted known gene in human cancer. The consequences of its disruption are profound, either in the germlines of patients with Li-Fraumeni Syndrome, or in mice with targeted gene knockouts. Abundant evidence suggests that p53 exerts regulation of cell cycle progression as well as apoptotic cell death, both in response to identical environmental or metabolic stressors. The specific decision of cell cycle arrest vs. death may underlie p53's differential ability to trigger death in cancer cells and arrest with repair in non-cancer cells, thus producing a therapeutic index pertinent to cancer therapy. Indeed, p53 status is likely to correlate with prognosis in many human cancers and in multiple animal tumor models. The mechanistic basis for p53's functions are still emerging, and will hopefully yield new therapeutic strategies applicable to treatment of the many poor-prognosis, p53-deficient human malignancies.     

新的抑癌基因ASPP对p53作用的研究进展

p53是一个肿瘤抑制蛋白,它是通过调节相关基因表达,诱导细胞凋亡。p53诱导细胞凋亡的机制多年来一直不太清楚,而最近发现的ASPP(apoptosis stimulating protein of p53)蛋白家族对p53诱导细胞凋亡的机制研究有了新的进展。本文就此作一综述。     

Chaperoning the guardian of the genome. The two-faced role of molecular chaperones in p53 tumor suppressor action

Organized networks of heat shock proteins, which possess molecular chaperone activity, protect cells from abrupt environmental changes. Additionally, molecular chaperones are essential during stress-free periods, where they moderate housekeeping functions. During tumorigenesis, these chaperone networks are extensively remodeled in such a way that they are advantageous to the transforming cell. Molecular chaperones by buffering critical elements of signaling pathways empower tumor evolution leading to chemoresistance of cancer cells. Controversially, the same molecular chaperones, which are indispensable for p53 in reaching its tumor suppressor potential, are beneficial in adopting an oncogenic gain of function phenotype when TP53 is mutated. On the molecular level, heat shock proteins by unwinding the mutant p53 protein expose aggregation-prone sites leading to the sequestration of other tumor suppressor proteins causing inhibition of apoptosis and chemoresistance. Therefore, within this review therapeutic approaches combining classical immuno- and/or chemotherapy with specific inhibition of selected molecular chaperones shall be discussed.     

p53 arrests growth and induces differentiation of v-Myb-transformed monoblasts

Abstract The p53 protein can control cell cycle progression, programmed cell death, and differentiation of many cell types. Ectopic expression of p53 can resume capability of cell cycle arrest, differentiation, and apoptosis in various leukemic cell lines. In this work, we expressed human p53 protein in v-Myb-transformed chicken monoblasts. We found that even this protein possessing only 53% amino acid homology to its avian counterpart can significantly alter morphology and physiology of these cells causing the G2-phase cell cycle arrest and early monocytic differentiation. Our results document that the species-specific differences of the p53 molecules, promoters/enhancers, and co-factors in avian and human cells do not interfere with differentiation- and cell cycle arrest promoting capabilites of the p53 tumor suppressor even in the presence of functional v-Myb oncoprotein. The p53-induced differentiation and cell cycle arrest of v-Myb-transformed monoblasts are not associated with apoptosis suggesting that the p53-driven pathways controlling apoptosis and differentiation/proliferation are independent.