p53 Induced Growth Arrest versus Apoptosis and its Modulation by Survival Cytokines

Liebermann, Dan A.; Hoffman, Barbara; Vesely, Diana L.

doi:10.4161/cc.6.2.3789

Cited by 74 publications

(57 citation statements)

References 56 publications

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“…Importantly, p53 does not seem to affect cell survival in these cells as shown by in the analysis of apoptotic nuclei and caspase-3 expression. This is in agreement with the evidence that p53-dependent cell death is typically present only in highly damaged cells, for example following high levels of genotoxic and oxidative stress or growth factor deficiency, which are known to trigger p53-dependent ap- optosis (Aloyz et al, 1998;Sakaguchi et al, 1998;Culmsee and Mattson, 2005;Liebermann et al, 2007).…”

Section: Discussionsupporting

confidence: 78%

“…In mitotic cells and in cancer, p53 has been shown (1) to negatively regulate cell proliferation through the transcriptional regulation of cell cycle arrest genes, such as p21 (Liebermann et al, 2007;Abbas and Dutta, 2009), and (2) to mediate cell death in highly damaged cells following a variety of stressors, including oxidative stress, DNA damage, and growth factor deprivation (Aloyz et al, 1998;Sakaguchi et al, 1998;Culmsee and Mattson, 2005).…”

Section: Introductionmentioning

confidence: 99%

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p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

et al. 2012

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Following spinal trauma, the limited physiological axonal sprouting that contributes to partial recovery of function is dependent upon the intrinsic properties of neurons as well as the inhibitory glial environment. The transcription factor p53 is involved in DNA repair, cell cycle, cell survival, and axonal outgrowth, suggesting p53 as key modifier of axonal and glial responses influencing functional recovery following spinal injury. Indeed, in a spinal cord dorsal hemisection injury model, we observed a significant impairment in locomotor recovery in p53 Ϫ/Ϫ versus wild-type mice. p53 Ϫ/Ϫ spinal cords showed an increased number of activated microglia/macrophages and a larger scar at the lesion site. Loss-and gain-of-function experiments suggested p53 as a direct regulator of microglia/macrophages proliferation. At the axonal level, p53 Ϫ/Ϫ mice showed a more pronounced dieback of the corticospinal tract (CST) and a decreased sprouting capacity of both CST and spinal serotoninergic fibers. In vivo expression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53 Ϫ/Ϫ mice, while, similarly, p53 expression in p53 Ϫ/Ϫ cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons. In conclusion, we show that p53 plays an important regulatory role at both extrinsic and intrinsic levels affecting the recovery of motor function following spinal cord injury. Therefore, we propose p53 as a novel potential multilevel therapeutic target for spinal cord injury.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

et al. 2012

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“…5A). Expression of the oncogene cyclin-D1 as well as phosphorylation of STAT3, which were reported to be regulated by p53 (34,35), were also markedly inhibited by MPHOSPH1 knockdown, suggesting that STAT3 activation was blocked through the p53 pathway. A probable mechanism was proposed previously by Blagosklonny (33), suggesting that during the mitotic arrest when the nuclear envelope is dissolved and chromosomes are condensed, transcription is absent, while the p53 mRNA is longlived and accumulates ( Fig.…”

Section: Discussionmentioning

confidence: 81%

MPHOSPH1: A Potential Therapeutic Target for Hepatocellular Carcinoma

et al. 2014

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MPHOSPH1 is a critical kinesin protein that functions in cytokinesis. Here, we show that MPHOSPH1 is overexpressed in hepatocellular carcinoma (HCC) cells, where it is essential for proliferation. Attenuating MPHOSPH1 expression with a tumor-selective shRNA-expressing adenovirus (Ad-shMPP1) was sufficient to arrest HCC cell proliferation in a manner associated with an accumulation of multinucleated polyploid cells, induction of postmitotic apoptosis, and increased sensitivity to taxol cytotoxicity. Mechanistic investigations showed that attenuation of MPHOSPH1 stabilized p53, blocked STAT3 phosphorylation, and prolonged mitotic arrest. In a mouse subcutaneous xenograft model of HCC, tumoral injection of Ad-shMPP1 inhibited MPHOSPH1 expression and tumor growth in a manner correlated with induction of apoptosis. Combining Ad-shMPP1 injection with taxol administration enhanced antitumor efficacy relative to taxol alone. Furthermore, Ad-shMPP1 tail vein injection suppressed formation of orthotopic liver nodules and prevented hepatic dysfunction. Taken together, our results identify MPHOSPH1 as an oncogenic driver and candidate therapeutic target in HCC. Cancer Res; 74(22); 6623-34. Ó2014 AACR.

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“…This may be dose dependent, as stochastic assembly of fewer wild-type p53 tetramers may lead to senescence not apoptosis. In vitro studies suggest that the intracellular level of activated p53 affects promoter binding and transactivation (25,26). A high level of active p53 initiates apoptosis because low-affinity p53 binding sites present in promoters of apoptosis-related genes are activated.…”

Section: Discussionmentioning

confidence: 99%

Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation

Wang¹,

Suh²,

Fuller³

et al. 2011

J. Clin. Invest.

117

105

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The transcription factor p53 is a tumor suppressor. As such, the P53 gene is frequently altered in human cancers. However, over 80% of the P53 mutations found in human cancers are missense mutations that lead to expression of mutant proteins that not only lack p53 transcriptional activity but exhibit new functions as well. Recent studies show that restoration of p53 expression leads to tumor regression in mice carrying p53 deletions. However, the therapeutic efficacy of restoring p53 expression in tumors containing p53 missense mutations has not been evaluated. Here we demonstrate that restoring wild-type p53 expression halted tumor growth in mice inheriting a p53 R172H missense mutation that is equivalent to a P53 missense mutation detected in approximately 6% of human cancers. However, it did not lead to tumor regression, as was observed in mice lacking p53. We further showed that the dominant-negative effect of the mutant p53 encoded by p53 R172H dampened the activity of the restored wild-type p53. We therefore conclude that in a mutant p53 background, p53 restoration has the therapeutic potential to suppress tumor progression. Our findings support using p53 restoration as a strategy to treat human cancers with P53 missense mutations and provide direction for optimizing p53 restoration in cancer therapy. IntroductionThe tumor suppressor p53 is a transcription factor. Upon activation by signals, such as DNA damage, oncogenic stimuli, and hypoxia, wild-type p53 activates the transcription of genes involved in apoptosis, cell cycle arrest, differentiation, and senescence (1, 2). These potent antitumor activities prevent cells with aberrant growth signals from proliferating. Approximately, half of human cancers have P53 gene alterations that result in loss of p53 activity. While a few of these alterations are P53-null mutations, over 80% are P53 missense mutations that lead to expression of mutant p53 proteins (3, 4). Many p53 missense mutants lack p53 transcriptional activity and show gain-of-function activities.In particular, the arginine-to-histidine mutation at codon 175 of the P53 gene (corresponding to p53 R172H in mice) occurs in about 6% of human cancers (5). The p53 R172H mutation has gain-of-function properties, manifested as a tumor metastasis phenotype in p53 R172H heterozygous mice that is lacking in p53 +/-mice (6, 7). Another property of the p53R172H mutant is its dominant-negative effect that silences wild-type p53 under some circumstances (8). Thus, for example, in response to γ-irradiation, mutant p53R172H inactivates wild-type p53 activities (9). Additionally, mutant p53 binds and suppresses the activities of the related proteins, p63 and p73 (7). However, the p53 R172H heterozygous mice that express equal amounts of wild-type and mutant p53 have survival curves identical to those of p53 +/-mice, indicating that

show abstract

p53 Induced Growth Arrest versus Apoptosis and its Modulation by Survival Cytokines

Cited by 74 publications

References 56 publications

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

MPHOSPH1: A Potential Therapeutic Target for Hepatocellular Carcinoma

Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation

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