Multifactorial analysis of <i>p53</i> alteration in human cancer: A review

Soussi, Thierry; Legros, Yann; Lubin, R.; Ory, Katherine; Schlichtholz, Beata

doi:10.1002/ijc.2910570102

Cited by 293 publications

(54 citation statements)

References 67 publications

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“…On the multivariate analysis, methylation of the ASPP1 gene promoter was an independent poor prognosis factor in ALL patients. Our results demonstrate that decreased expression of ASPP1 in patients with ALL is due to an abnormal methylation of its promoter and is associated with a poor prognosis.Oncogene ( Mutations of TP53 may result in an inhibition of protein function, which is associated with tumor progression and genetic instability (Caron de Fromentel and Soussi, 1992;Hollstein et al, 1994;Soussi et al, 1994). Although 40-50% of human tumors have mutations on TP53, the percentage of mutations in patients with leukemia is significantly lower (less that 10%), suggesting that other mechanisms may be involved in the inability of p53 to induce apoptosis since p53 does not suppress tumor growth or induce apoptosis in tumors with wild-type TP53.…”

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confidence: 99%

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

et al. 2006

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We have analyzed the regulation and expression of ASPP members, genes implicated in the regulation of the apoptotic function of the TP53 tumor-suppressor gene, in acute lymphoblastic leukemia (ALL). Expression of ASPP1 was significantly reduced in ALL and was dependent on hypermethylation of the ASPP1 gene promoter. Abnormal ASPP1 expression was associated with normal function of the tumor-suppressor gene TP53 in ALL. The analyses of 180 patients with ALL at diagnosis showed that the ASPP1 promoter was hypermethylated in 25% of cases with decreased mRNA expression. Methylation was significantly higher in adult ALL vs childhood ALL (32 vs 17%, P ¼ 0.03) and T-ALL vs B-ALL (50 vs 9%, P ¼ 0.001). Relapse rate (62 vs 44%, P ¼ 0.05) and mortality (59 vs 43%, P ¼ 0.05) were significantly higher in patients with methylated ASPP1. DFS and OS were 32.8 and 33.7% for patients with unmethylated ASPP1 and 6.1 and 9.9% for methylated patients (Po0.001 y Po0.02, respectively). On the multivariate analysis, methylation of the ASPP1 gene promoter was an independent poor prognosis factor in ALL patients. Our results demonstrate that decreased expression of ASPP1 in patients with ALL is due to an abnormal methylation of its promoter and is associated with a poor prognosis.Oncogene ( Mutations of TP53 may result in an inhibition of protein function, which is associated with tumor progression and genetic instability (Caron de Fromentel and Soussi, 1992;Hollstein et al., 1994;Soussi et al., 1994). Although 40-50% of human tumors have mutations on TP53, the percentage of mutations in patients with leukemia is significantly lower (less that 10%), suggesting that other mechanisms may be involved in the inability of p53 to induce apoptosis since p53 does not suppress tumor growth or induce apoptosis in tumors with wild-type TP53.The recently described ASPP family of proteins comprised of ASPP1, ASPP2 and iASPP has been implicated in the apoptotic function of TP53 and p53 family members TP73L (p63) and TP73 (Bergamaschi et al., 2004). Different studies have shown that ASPP1 and ASPP2 increase the apoptotic effect of p53 by inducing the transcription of proapoptotic genes such as BAX and PIG3 mediated by TP53, while they have no influence on the transcription of MDM2 and CDKN1A (p21, Cip1), which mediate p53-dependent cell cycle arrest (Samuels-Lev et al., 2001;Slee and Lu, 2003;Bergamaschi et al., 2004). Transactivation of TP53-mediated transcription of proapoptotic genes mediated by ASPP1 and ASPP2 is completely abolished by increased expression of the evolutionary conserved TP53 inhibitor and third member of the ASPP family, iASPP (Bergamaschi et al., 2003).It has been hypothesized that in wild-type TP53 tumors, alterations of ASPP1 and/or ASPP2, can produce a selective advantage due to the lack of stimulation of apoptosis (Samuels-Lev et al., 2001;Slee and Lu, 2003;Bergamaschi et al., 2004). Samuels-Lev et al. (2001) These two authors contributed equally to this work.

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ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

et al. 2006

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“…The tumor suppressor p53 plays a pivotal role for the fate of a cell since it prevents cell cycle progression or induces apoptosis when cells are exposed to genotoxic or hypoxic stress or suboptimal growth conditions (for review, see Soussi et al, 1994 andHansen andOren, 1997). Its misfunction is associated with many tumor incidences in human.…”

Section: Introductionmentioning

confidence: 99%

Expression of human p53 requires synergistic activation of transcription from the p53 promoter by AP-1, NF-κB and Myc/Max

et al. 1999

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Transcriptional control of p53 expression participates in the generation of appropriate levels of active p53 in response to mitogenic stimulation. This prompted us to study the role of a putative AP-1 and a NF-kB motif in the human p53 promoter for transcriptional regulation. We show that mutation of the AP-1 or the NF-kB motif abolishes transcription from the human p53 promoter in HeLa, HepG2 and adenovirus type 5 E1-transformed 293 cells. In comparison, mutation of the previously characterized Myc/Max/USF binding site in the human p53 promoter reduces the transcription rate ®vefold. The AP-1 motif in the human p53 promoter binds c-Fos and c-Jun and the NF-kB motif binds p50 NF-kB1 and p65 RelA . The cooperative nature of transcriptional activation by these factors was documented by repression of c-fos or NF-kB1 translation: Pretreatment of the cells with a cfos or p50 NF-kB1 antisense oligonucleotide suppresses transcription from the human p53 promoter completely. In addition, we show that (a) the level of endogenous p53 mRNA and (b) transcription from the strictly p53-dependent human mdm2 promoter are reduced in the presence of c-fos, c-jun, p50 NF-kB1 , p65 RelA or c-myc antisense oligonucleotides, underscoring the importance of these transcription factors for the expression of functional p53.

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“…Deletion of the TP53 gene in transgenic mice results in a massive increase tumour incidence (Donehower et al, 1992), supporting a role for p53 as a tumour suppressor. The p53 functions appear to be inactivated in a very large range of human cancers (Hollstein et al, 1991;Soussi et al, 1994). The most frequent form of this inactivation is genetic alteration which results in altered conformation of the protein (Levine et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

p21WAF1/CIP1 response to genotoxic agents in wild-type TP53 expressing breast primary tumours

et al. 1997

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Functional inactivation of the wild-type p53 protein has been described in di erent human cancers. Since a signi®cant proportion of breast tumours express wildtype TP53, the p53 antiproliferative activity could be inactivated in transformed mammary epithelial cells by a mechanism independent on structural alteration of the gene. To test this hypothesis, we analysed the p53 activity in primary breast tumour cells. As a preliminary study, we demonstrated in breast adenocarcinoma cell lines that the nuclear accumulation of the inhibitor of cyclin dependent kinase p21 WAF1/CIP1 , in response to adriamycin treatment, speci®cally re¯ected the activity of a functional wild-type p53 protein. Then, we used this strategy to study the p53 activity in 23 primary breast tumours. p21 WAF1/CIP1 accumulation was detected in all tumours expressing wild-type TP53. In contrast, no p21 WAF1/CIP1 response was detected in cells harboring a mutant TP53 gene. This report is the ®rst functional study of p53 in primary breast tumours. The results demonstrate that TP53 mutation represents the only common mechanism leading to an irreversible inactivation of p53 functions in this cancer type.

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Multifactorial analysis of p53 alteration in human cancer: A review

Cited by 293 publications

References 67 publications

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia

Expression of human p53 requires synergistic activation of transcription from the p53 promoter by AP-1, NF-κB and Myc/Max

p21WAF1/CIP1 response to genotoxic agents in wild-type TP53 expressing breast primary tumours

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