Directing p53 to induce autophagy

Comment on: Naidu SR, et al. Cell Cycle 2012; 11:2717-28.     

Regulation of cellular senescence by p53.

Many normal cells respond to potentially oncogenic stimuli by undergoing cellular senescence, a state of irreversibly arrested proliferation and altered differentiated function. Cellular senescence very likely evolved to suppress tumorigenesis. In support of this idea, it is regulated by several tumor suppressor genes. At the heart of this regulation is p53. p53 is essential for the senescence response to short telomeres, DNA damage, oncogenes and supraphysiological mitogenic signals, and overexpression of certain tumor suppressor genes. Despite the well-documented central role for p53 in the senescence response, many questions remain regarding how p53 senses senescence-inducing stimuli and how it elicits the senescent phenotype.     

调控p53蛋白的转录因子

肿瘤抑制因子p53被称为"分子警察",它在维持细胞正常生长及抑制恶性增殖过程中起重要作用。p53的表达水平受多种因素影响,其中转录水平的调控是基因发挥功能的一个重要步骤。因此,针对调控p53蛋白的转录因子这一环节阐明p53发挥功能的分子机理,有望为肿瘤治疗、预防和新药研发提供新的靶标。本文着重对调控p53蛋白的转录因子进行综述。     

Regulation of PTEN transcription by p53.

PTEN tumor suppressor is frequently mutated in human cancers and is a negative regulator of PI3'K/PKB/Akt-dependent cellular survival. Investigation of the human genomic PTEN locus revealed a p53 binding element directly upstream of the PTEN gene. Deletion and mutation analyses showed that this element is necessary for inducible transactivation of PTEN by p53. A p53-independent element controlling constitutive expression of PTEN was also identified. In contrast to p53 mutant cell lines, induction of p53 in primary and tumor cell lines with wild-type p53 increased PTEN mRNA levels. PTEN was required for p53-mediated apoptosis in immortalized mouse embryonic fibroblasts. Our results reveal a unique role for p53 in regulation of cellular survival and an interesting connection in tumor suppressor signaling.     

Regulation of p53 acetylation

正As agenomic guardian,the tumor suppressor p53 plays key roles in maintaining homeostasis under physiological conditions and defending against tumorigenesis upon cellular exposure to internal or external stresses.Appropriate regulation of p53 is essential to ensure appropriate p53function,and this process is highly dependent on dynamic posttranslational modification(PTM,including acetylation,phosphorylation,ubiquitination et al.)of p53 protein     

Regulation of p53 localization.

Despite intensive study of p53, the regulation of p53 cellular localization is still poorly understood. This is an overview of the elements and molecules involved in p53 nucleocytoplasmic transportation. These include the nuclear import and export signals of p53, inhibition of p53 nuclear import and export by oligomerization, MDM2-mediated p53 nuclear export, and possible roles of p53 phosphorylation in regulating p53 cellular localization. Finally, questions regarding p53 cellular trafficking will also be discussed.     

p53 Regulation of Metabolic Pathways

During the course of tumorigenesis, cells acquire a number of alterations that contribute to the acquisition of the malignant phenotype, allowing them to survive and flourish in increasingly hostile environments. Cancer cells can be characterized by perturbations in the control of cell proliferation and growth, resistance to death, and alterations in their interactions with the microenvironment. Underpinning many of these changes are shifts in metabolism that allow cancer cells to use alternative pathways for energy production and building the macromolecules necessary for growth, as well as regulating the generation of signaling molecules such as reactive oxygen species (ROS). In the past few years, it became clear that p53, the most studied, if not most important, tumor suppressor protein, can also directly control metabolic traits of cells.Given the importance of metabolic reprogramming in tumor development, it is no surprise that many oncogenes and tumor suppressor genes have been shown to help control these pathways (DeBerardinis et al. 2008a; Tennant et al. 2009). In most cases, these effects are fairly clear—proteins that can promote cancer development drive the metabolic transformation associated with malignancies and tumor suppressor proteins oppose these effects. p53 plays a central and key role in preventing cancer development (Vousden and Prives 2009), but the regulation of metabolism by p53 is proving to be far from straightforward. Although the explanation for this complexity is not clear, there are several obvious and ultimately testable models. What is evident, however, is that the regulation of metabolic pathways is an important facet of p53 function that may provide us with some novel and effective new therapeutic targets, for cancer and maybe also other diseases.     

A role of cytoplasmic p53 in the regulation of metabolism shown by bat-mimicking p53 NLS mutant mice

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Parc: a cytoplasmic anchor for p53

Nuclear localization of p53 is essential for its tumor suppressor function. Here, we have identified Parc, a Parkin-like ubiquitin ligase, as a cytoplasmic anchor protein in p53-associated protein complexes. Parc directly interacts and forms a approximately 1 MDa complex with p53 in the cytoplasm of unstressed cells. In the absence of stress, inactivation of Parc induces nuclear localization of endogenous p53 and activates p53-dependent apoptosis. Overexpression of Parc promotes cytoplasmic sequestration of ectopic p53. Furthermore, abnormal cytoplasmic localization of p53 was observed in a number of neuroblastoma cell lines; RNAi-mediated reduction of endogenous Parc significantly sensitizes these neuroblastoma cells in the DNA damage response. These results reveal that Parc is a critical regulator in controlling p53 subcellular localization and subsequent function.     

Regulation of the DNA damage response by p53 cofactors

The selective expression of p53-targeted genes is central to the p53-mediated DNA damage response. It is affected by multiple factors including posttranslational modifications and cofactors of p53. Here, we proposed an integrated model of the p53 network to characterize how the cellular response is regulated by key cofactors of p53, Hzf and ASPP. We found that the sequential induction of Hzf and ASPP is crucial to a reliable cell-fate decision between survival and death. After DNA damage, activated p53 first induces Hzf, which promotes the expression of p21 to arrest the cell cycle and facilitate DNA repair. The cell recovers to normal proliferation after the damage is repaired. If the damage is beyond repair, Hzf is effectively degraded, and activated E2F1 induces ASPP, which promotes the expression of Bax to trigger apoptosis. Furthermore, interrupting the induction of Hzf or ASPP remarkably impairs the cellular function. We also proposed two schemes for the production of the unknown E3 ubiquitin ligase for Hzf degradation: it is induced by either E2F1 or p53. In both schemes, the sufficient degradation of Hzf is required for apoptosis induction. These results are in good agreement with experimental observations or are experimentally testable.     

hGTSE-1 expression stimulates cytoplasmic localization of p53

hGTSE-1 (human G(2) and S phase-expressed-1) is a cell cycle-regulated protein mainly localized in the cytoplasm and apparently associated with the microtubules. hGTSE-1 is able to down-regulate levels and activity of the p53 tumor suppressor protein: it binds the C-terminal region of p53 and represses its ability to induce apoptosis after DNA damage. Here we report that, after DNA damage, hGTSE-1 becomes stabilized in a p53-independent way and accumulated in the nucleus. Further characterization of hGTSE-1 localization revealed increased nuclear staining in unstressed cells after treatment with the nuclear export inhibitor leptomycin B, or when a nuclear export signal (NES) located in its C-terminal region was mutated. Finally, we provide evidence that hGTSE-1 ectopic expression, in addition to p53 protein levels down-regulation, is able to enhance cytoplasmic localization of p53. Interestingly, NES-mutated hGTSE-1 accumulates in the nucleus, binds p53 but looses its ability to enhance cytoplasmic redistribution of p53 and to regulate p53 protein levels. Similarly, when wild type hGTSE-1 functions on p53 were analyzed in cells lacking Mdm2, it failed in regulating both p53 localization and protein levels, thus indicating that hGTSE-1 requires an intact NES and functional Mdm2 for the regulation of p53. Our results provide new insights into the mechanism of hGTSE-1 function, whereby its characterized nucleo-cytoplasmic shuttling ability is required to regulate p53.