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MDM2 is a ubiquitin ligase that plays a key role in regulating the stability of the p53 tumor suppressor protein. Several proteins have been shown to activate the p53 pathway by interacting with and inhibiting the E3 function of MDM2, thereby leading to an accumulation of p53. These include the alternate reading frame (ARF) proteins and the ribosomal proteins L5 and L11. We found that when overexpressed alone, L11 is much less potent in inhibiting MDM2 than p14ARF. However, L11 cooperates with L5, resulting in a robust inhibition of the E3 activity of MDM2, and a stabilization and activation of p53 approaching that achieved by p14ARF. We further showed that the ability of L11 to bind the 5S rRNA is important for the cooperation with L5, and a mutant L11, which cannot bind the 5S rRNA, cannot cooperate with L5 in inhibiting MDM2.Oncogene (2008) 27, 5774–5784; doi:10.1038/onc.2008.189; published online 16 June 2008 [ABSTRACT FROM AUTHOR]

Over the years, p53 has been shown to sit at the centre of an increasingly complex web of incoming stress signals and outgoing effector pathways. The number and diversity of stress signals that lead to p53 activation illustrates the breadth of p53's remit – responding to a wide variety of potentially oncogenic insults to prevent tumour development. Interestingly, different stress signals can use different and independent pathways to activate p53, and there is some evidence that different stress signals can mediate different responses. How each of the responses to p53 contributes to inhibition of malignant progression is beginning to be clarified, with the hope that identification of responses that are key to tumour suppression will allow a more focused and effective search for new therapeutic targets. In this review, we will highlight some recently identified roles for p53 in tumour suppression, and discuss some of the numerous mechanisms through which p53 can be regulated and activated.Oncogene (2007) 26, 1306–1316. doi:10.1038/sj.onc.1210263 [ABSTRACT FROM AUTHOR]

The p53 tumour suppressor protein inhibits malignant progression by mediating cell cycle arrest, apoptosis or repair following cellular stress. One of the major regulators of p53 function is the MDM2 protein, and multiple forms of cellular stress activate p53 by inhibiting the MDM2-mediated degradation of p53. Mutations in p53, or disruption of the pathways that allow activation of p53, seem to be a general feature of all cancers. Here we review recent advances in our understanding of the pathways that regulate p53 and the pathways that are induced by p53, as well as their implications for cancer therapy. [ABSTRACT FROM AUTHOR]

Regulation of the p53 tumor suppressor protein occurs to a large extent through control of protein stability, and the MDM2 protein has been shown to play a key role in targeting p53 for degradation. Stress signals that activate the p53 response lead to stabilization of p53 through inhibition of MDM2 mediated degradation, and it is becoming evident that a number of mechanisms exist to abrogate this activity of MDM2. Other members of the p53 protein family may also be regulated through protein stability, although MDM2 is not responsible for the degradation of p73. [ABSTRACT FROM AUTHOR]

A variant (HPV16b) of the previously described human papillomavirus (HPV)16 (now called HPV16a) has been identified by polymerase chain reaction assays. Compared with HPV16a, HPV16b has a 21bp deletion and several point mutations within the upstream regulatory region. All cervical carcinoma samples studied contained only HPV16a. HPV16b was found only rarely in cervical neoplasia but was common in the normal population. [ABSTRACT FROM AUTHOR]

The article discusses the correlation of PFK-1 activity with changes in cellular metabolism and physiology. It notes that PFK-1 activity is characteristic of cancer cells and is tightly regulated due to its functions as gatekeeper to glycolysis. It cites the role of TIGAR, a recently identified F2,6 biphosphatase, in limiting glycolysis and thus shift the balance away from aerobic glycolysis commonly seen in cancers.

Many cancers express mutant p53 proteins that have lost wild-type tumor suppressor activity and, in many cases, have acquired oncogenic functions that can contribute to tumor progression. These activities of mutant p53 reflect interactions with several other proteins, including the p53 family members p63 and p73. Mutations in p53 that affect protein conformation (such as R175H) show strong binding to p63 and p73, whereas p53 mutants that only mildly affect the conformation (such as R273H) bind less well. A previously described aggregation domain of mutant p53 is not required for p63 or p73 binding; indeed, mutations within this region lead to the acquisition of a mutant p53 phenotype-including a conformational shift, p63/p73 binding and the ability to promote invasion. The activity of wild-type p53 is regulated by an interaction with MDM2 and we have investigated the potential role of MDM2 in the mutant p53/p63/p73 interactions. Both mutant p53 and p73 bind MDM2 well, whereas p63 binds much more weakly. We found that MDM2 can inhibit p63 binding to p53R175H but enhances the weaker p53R273H/p73 interaction. These effects on the interactions are reflected in an ability of MDM2 to relieve the inhibition of p63 by p53R175H, but enhance the inhibition of p73 activity by p53R175H and R273H. We propose a model in which MDM2 competes with p63 for binding to p53R175H to restore p63 activity, but forms a trimeric complex with p73 and p53R273H to more strongly inhibit p73 function. [ABSTRACT FROM AUTHOR]

Many tumours harbour mutations in the p53 tumour-suppressor gene that result in the expression of a mutant p53 protein. This mutant p53 protein has, in most cases, lost wild-type transcriptional activity and can also acquire novel functions in promoting invasion and metastasis. One of the mechanisms underlying these novel functions involves the ability of the mutant p53 to interfere with other transcription factors, including the p53 family protein TAp63. To investigate whether simultaneous depletion of both p53 and TAp63 can recapitulate the effect of mutant p53 expression in vivo, we used a mouse model of pancreatic cancer in which the expression of mutant p53 resulted in the rapid appearance of primary tumours and metastases. As shown previously, loss of one allele of wild-type (WT) p53 accelerated tumour development. A change of one WT p53 allele into mutant p53 did not further accelerate tumour development, but did promote the formation of metastasis. By contrast, loss of TAp63 did not significantly accelerate tumour development or metastasis. However, simultaneous depletion of p53 and TAp63 led to both rapid tumour development and metastatic potential, although the incidence of metastases remained lower than that seen in mutant p53-expressing tumours. TAp63/p53-null cells derived from these mice also showed an enhanced ability to scatter and invade in tissue culture as was observed in mutant p53 cells. These data suggest that depletion of TAp63 in a p53-null tumour can promote metastasis and recapitulate--to some extent--the consequences of mutant p53 expression. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that C-MYC may be an excellent therapeutic cancer target and a number of new agents targeting C-MYC are in preclinical development. Given most therapeutic regimes would combine C-MYC inhibition with genotoxic damage, it is important to assess the importance of C-MYC function for DNA damage signalling in vivo. In this study, we have conditionally deleted the c-Myc gene in the adult murine intestine and investigated the apoptotic response of intestinal enterocytes to DNA damage. Remarkably, c-Myc deletion completely abrogated the immediate wave of apoptosis following both ionizing irradiation and cisplatin treatment, recapitulating the phenotype of p53 deficiency in the intestine. Consistent with this, c-Myc-deficient intestinal enterocytes did not upregulate p53. Mechanistically, this was linked to an upregulation of the E3 Ubiquitin ligase Mdm2, which targets p53 for degradation in c-Myc-deficient intestinal enterocytes. Further, low level overexpression of c-Myc, which does not impact on basal levels of apoptosis, elicited sustained apoptosis in response to DNA damage, suggesting c-Myc activity acts as a crucial cell survival rheostat following DNA damage. We also identify the importance of MYC during DNA damage-induced apoptosis in several other tissues, including the thymus and spleen, using systemic deletion of c-Myc throughout the adult mouse. Together, we have elucidated for the first time in vivo an essential role for endogenous c-Myc in signalling DNA damage-induced apoptosis through the control of the p53 tumour suppressor protein. [ABSTRACT FROM AUTHOR]

Tumour-derived mutant p53 proteins promote invasion, in part, by enhancing Rab coupling protein (RCP)-dependent receptor recycling. Here we identified MET as an RCP-binding protein and showed that mutant p53 promoted MET recycling. Mutant p53-expressing cells were more sensitive to hepatocyte growth factor, the ligand for MET, leading to enhanced MET signalling, invasion and cell scattering that was dependent on both MET and RCP. In cells expressing the p53 family member TAp63, inhibition of TAp63 also lead to cell scattering and MET-dependent invasion. However, in cells that express very low levels of TAp63, the ability of mutant p53 to promote MET-dependent cell scattering was independent of TAp63. Taken together, our data show that mutant p53 can enhance MET signalling to promote cell scattering and invasion through both TAp63-dependent and -independent mechanisms. MET has a predominant role in metastatic progression and the identification of mechanisms through which mutations in p53 can drive MET signalling may help to identify and direct therapy. [ABSTRACT FROM AUTHOR]

The p53-inducible BH3-only protein PUMA is a key mediator of p53-dependent apoptosis, and PUMA has been shown to function by activating Bax and mitochondrial outer membrane permeabilization. In this study, we describe an ability of PUMA to induce autophagy that leads to the selective removal of mitochondria. This function of PUMA depends on Bax/Bak and can be reproduced by overexpression of Bax. The induction of autophagy coincides with cytochrome c release, and taken together the results suggest that PUMA functions through Bax to induce mitochondrial autophagy in response to mitochondrial perturbations. Surprisingly, inhibition of PUMA or Bax-induced autophagy dampens the apoptotic response, suggesting that under some circumstances the selective targeting of mitochondria for autophagy can enhance apoptosis.Cell Death and Differentiation (2009) 16, 1135–1145; doi:10.1038/cdd.2009.28; published online 20 March 2009 [ABSTRACT FROM AUTHOR]

The E2F family of transcription factors regulates the expression of a number of genes whose products are involved in cell cycle control, DNA replication and apoptosis. We show here that E2F-1 binds in vivo the promoters of ASPP1 and ASPP2 genes, two activators of p53-mediated apoptosis, E2F-1, E2F-2 and E2F-3 all activate the isolated ASPP1 and ASPP2 promoters. Overexpression or deregulation of E2F-1 increased the expression levels of ASPP1 and ASPP2 mRNA and proteins. The identification of ASPP1 and ASPP2 genes as transcriptional targets of E2F provides another mechanism by which E2F cooperates with p53 to induce apoptosis.Cell Death and Differentiation (2005) 12, 369-376. doi:10.1038/sj.cdd.4401562 Published online 25 February 2005 [ABSTRACT FROM AUTHOR]

In common with other E2F1 responsive genes such as p14(ARF) and B-myb, the promoter of p73 is shown to be positively regulated in cell lines and primary human keratinocytes by E7 proteins from oncogenic human papillomavirus (HPV) types 16, 18, 31 and 33, but not HPV 6. Mutational analysis revealed that transactivation of the p73 promoter by HPV 16E7 requires association with pRb. Expression of p73 in normal cervical epithelium is confined to the basal and supra-basal layers. In contrast, expression in neoplastic lesions is detected throughout the epithelium and increases with grade of neoplasia, being maximal in squamous cell cancers (SCC). Deregulation of expression of the N-terminal splice variant p73Delta2 was observed in a significant proportion of cancers, but not in normal epithelium. The frequent over-expression of p73Delta2, which has recognized transdominant properties, in malignant and pre-malignant lesions suggests a role in the oncogenic process in cervical epithelium. [ABSTRACT FROM AUTHOR]