A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Ras-induced transformation

Boiko, Alexander D.; Porteous, Sarah; Razorenova, Olga V.; Krivokrysenko, Vadim I.; Williams, Bryan R.G.; Gudkov, Andrei V.

doi:10.1101/gad.1372606

Cited by 123 publications

(114 citation statements)

References 77 publications

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“…First, we confirmed that mycoplasma infection in fact resulted in decreased p53-dependent transcription of p21 waf1 in REF52 cells as it did in the other cell lines tested above (Figure 4a). Next, we prepared a variant of REF52 cells (REF52/sh-p53) in which p53 expression is reduced due to lentiviral transduction of shRNA against p53 (Boiko et al, 2006). shRNA-mediated knockdown of p53 expression was confirmed by semiquantative RT-PCR analysis of p53 mRNA levels (Figure 4b).…”

Section: Resultsmentioning

confidence: 99%

Mycoplasma infection suppresses p53, activates NF-κB and cooperates with oncogenic Ras in rodent fibroblast transformation

et al. 2008

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Prokaryotes of the genus Mycoplasma are the smallest cellular organisms that persist as obligate extracellular parasites. Although mycoplasma infection is known to be associated with chromosomal instability and can promote malignant transformation, the mechanisms underlying these phenomena remain unknown. Since persistence of many cellular parasites requires suppression of apoptosis in host cells, we tested the effect of mycoplasma infection on the activity of the p53 and nuclear factor (NF)-jB pathways, major mechanisms controlling programmed cell death. To monitor the activity of p53 and NF-jB in mycoplasma-infected cells, we used a panel of reporter cell lines expressing the bacterial b-galactosidase gene under the control of p53-or NF-jB-responsive promoters. Cells incubated with media conditioned with different species of mycoplasma showed constitutive activation of NF-jB and reduced activation of p53, common characteristics of the majority of human tumor cells, with M. arginini having the strongest effect among the species tested. Moreover, mycoplasma infection reduced the expression level and inducibility of an endogenous p53-responsive gene, p21 waf1 , and inhibited apoptosis induced by genotoxic stress. Infection with M. arginini made rat and mouse embryo fibroblasts susceptible to transformation with oncogenic H-Ras, whereas mycoplasma-free cells underwent irreversible p53-dependent growth arrest. Mycoplasma infection was as effective as shRNA-mediated knockdown of p53 expression in making rodent fibroblasts permissive to Rasinduced transformation. These observations indicate that mycoplasma infection plays the role of a p53-suppressing oncogene that cooperates with Ras in cell transformation and suggest that the carcinogenic and mutagenic effects of mycoplasma might be due to inhibition of p53 tumor suppressor function by this common human parasite.

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Section: Resultsmentioning

confidence: 99%

Mycoplasma infection suppresses p53, activates NF-κB and cooperates with oncogenic Ras in rodent fibroblast transformation

et al. 2008

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“…Wild-type p53 repressed CGS expression by mechanisms involving the p53 targets BTG2 and ATF3, previously described as involved in Ras-induced transformation. 29,30 ATF3 directly binds to the CGS promoters and represses their expression, while BTG2 interacts with H-Ras and represses its activity. 31 This effect may represent a novel suppressive function of wild-type p53.…”

Section: The P53 Pathway: From Normal To Tumor Cellsmentioning

confidence: 99%

Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies

et al. 2010

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Three decades of p53 research have led to many advances in understanding the basic biology of normal and cancer cells. Nonetheless, the detailed functions of p53 in normal cells, and even more so in cancer cells, remain obscure. A major breakthrough is the realization that mutant p53 has a life of its own: it contributes to cancer not only through loss of activity, but also through gain of specific 'mutant functions'. This new focus on mutant p53 is the rationale behind the meeting series dedicated to advances on mutant p53 biology. This review provides an overview of results presented at the Fourth International Workshop on Mutant p53, held in Akko, Israel in March 2009. New roles and functions of p53 relevant for tumor suppressions were presented, including the regulation of microRNAs networks, the modulation of cell-stroma interactions and the induction of senescence. A main focus of the meeting was the rapidly growing body of knowledge on autonomous properties of mutant p53 and on their oncogenic 'gain of function' impact. Importantly, the meeting highlighted that, 30 years after p53 discovery, research on mutant p53 is entering the clinical and translational era. Two major steps forward in this respect are a better understanding of the active mechanism of small drugs targeting mutant p53 in tumor cells and an improved definition of the prognostic and predictive value of mutant p53 in human cancer.

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“…Firstly, large-scale proteomic approaches may help identify splicing factors and their posttranslational modifications induced by Ca ++ signals. Secondly, whole genome RNA interference libraries have been developed recently and applied to whole genome loss-of-function screening of genes [215][216][217][218][219][220][221][222]. Screening for alternative splicing factors by RNAi has already been carried out in fly cells [215,216].…”

Section: Perspectivesmentioning

confidence: 99%

Control of alternative pre-mRNA splicing by Ca++ signals

Xie¹

2008

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Alternative pre-mRNA splicing is a common way of gene expression regulation in metazoans. The selective use of specific exons can be modulated in response to various manipulations that alter Ca ++ signals, particularly in neurons. A number of splicing factors have also been found to be controlled by Ca ++ signals. Moreover, pre-mRNA elements have been identified that are essential and sufficient to mediate Ca ++ -regulated splicing, providing model systems for dissecting the involved molecular components. In neurons, this regulation likely contributes to the fine-tuning of neuronal properties.

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A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Ras-induced transformation

Cited by 123 publications

References 77 publications

Mycoplasma infection suppresses p53, activates NF-κB and cooperates with oncogenic Ras in rodent fibroblast transformation

Mycoplasma infection suppresses p53, activates NF-κB and cooperates with oncogenic Ras in rodent fibroblast transformation

Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies

Control of alternative pre-mRNA splicing by Ca++ signals

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