p53 Mutations in Human Cancers

Hollstein, Monica; Sidransky, David; Vogelstein, Bert; Harris, Curtis C.

doi:10.1126/science.1905840

Cited by 7,225 publications

(4,299 citation statements)

References 70 publications

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“…Indeed, the p53 gene is one of the most frequently mutated genes in human malignancies (Hollstein et al, 1991;Levine et al, 1991;Vogelstein and Kinzler, 1992). Its product, the wild-type (WT) p53 protein, plays an important role in the cellular response to DNA damage by controlling cell cycle and allowing repair of the altered genome (Hartwell, 1992;Lane, 1992).…”

Section: Introductionmentioning

confidence: 99%

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

et al. 2000

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The tumor suppressor p53 plays a pivotal role in the cellular response to DNA damage as it controls DNA repair, cell cycle arrest and apoptosis. We studied the autoregulation of human p53 gene transcription in colon cancer cell lines. Wild-type p53 has been shown to autoregulate its own transcription either positively or negatively and probably in a cell-type-speci®c manner. Indeed, a p53 binding site has been described in the human and murine p53 promoters, but a direct binding of wild-type p53 protein to this site has never been reported.In this study, we demonstrated a transactivation of human p53 promoter by wild-type p53 in human colon cancer cells. We identi®ed in the human p53 promoter a novel potential p53-responsive element that binds wildtype p53. Moreover, wild-type p53 protein transactivated a reporter plasmid containing a luciferase gene driven by a minimal promoter harboring this p53 binding site. Finally, as the p53 promoter contains an NF-kB binding site, we demonstrated an additive e ect when NF-kB subunits and p53 protein combined to transactivate the human p53 promoter. Oncogene (2000) 19, 4787 ± 4794.

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Section: Introductionmentioning

confidence: 99%

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

et al. 2000

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“…5 Mutations and inactivation of the p53 tumor suppressor gene can result in loss of control of cell division, inappropriate stimulation of cell growth, increased cell survival and genetic instability resulting in the formation of tumors. 6,7 Mutation of p53 has been implicated in the development of cancers of the breast, colon, lung, prostate, bladder, skin, as well as hepatocellular carcinoma. 6,[8][9][10][11][12] The Ki-67 protein is associated with active cell proliferation.…”

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p53, Ki-67, and serum alpha feto-protein as predictors of hepatocellular carcinoma recurrence in liver transplant patients

et al. 2005

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Patients with hepatocellular carcinoma who undergo orthotopic liver transplantation (OLT) are at risk for posttransplant tumor recurrence. The aim of this study was to evaluate whether expression of p53 and Ki-67 in hepatocellular carcinoma lesions present in explanted liver tissue was associated with time to tumor recurrence after OLT. Subjects consisted of 20 consecutive patients who underwent OLT and were found to have hepatocellular carcinoma in the liver explant. Immunostaining for p53 and Ki-67 was performed by standard methods. The presence of nuclear immunostaining in 410% of the tumor tissue was considered positive. Time to recurrence of hepatocellular carcinoma after OLT was compared between patients with positive and negative immunostaining by the log rank test. Multivariate analysis was performed using a Cox regression model to control for potentially confounding clinical factors. Time to post-transplant hepatocellular carcinoma recurrence was significantly more rapid in p53 þ (P ¼ 0.0007) and Ki-67 þ cases (P ¼ 0.001). These associations remained significant in multivariate analysis. Furthermore, time to recurrent hepatocellular carcinoma was significantly shorter in patients with a serum alpha feto-protein (AFP) level Z100 ng/ml at time of diagnosis, compared to those with an AFP level o100 ng/ml (P ¼ 0.003). In conclusion, expression of p53 and Ki-67 in hepatocellular carcinoma lesions, and a serum AFP level Z100 ng/ml were associated with more rapid recurrence of hepatocellular carcinoma after OLT. Identification of patients at risk for early post-transplant recurrence could be used to guide surveillance and adjuvant treatment strategies.

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“…9 In a normal cell, p53 protein levels are quite low, but upon stress or DNA damage, the p53 protein is stabilized and becomes active. 10 The activity of the wild-type p53 protein includes transcriptional activation of key cell cycle and proapoptotic control genes, such as p21Waf1 11 and bax, 12,13 as well as the p53 antagonist, mdm2.…”

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confidence: 99%

A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition

2005

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Typically, gene transfer strategies utilize a promoter/transgene arrangement that treat these elements independently and do not offer any interplay between them. Our goal was to establish a promoter/transgene combination that would result in improvement in both expression and therapeutic effect by utilizing the transcriptional properties of p53 to drive its own expression as well as act as a tumor suppressor. The pCL retroviral system was modified in the U3 region of the 3 0 LTR by the addition of a p53-responsive sequence (the PG element), creating the pCLPG system. Upon reverse transcription, the 5 0 LTR is converted, as shown here, to a p53-dependent promoter. We also show, using a temperature-sensitive model, that the pCLPG system could be driven by p53 encoded within the virus construct and expression was modulated depending on the p53 phenotype, demonstrating a regulatory feedback loop. Moreover, the pCLPG system was shown to express the transgene at a higher level and to inhibit tumor cell proliferation more robustly than the original pCL system. This novel system employs the transgene to serve two purposes, drive viral expression and inhibit tumor cell proliferation. The pCLPG vectors represent a new gene transfer strategy of synergizing the promoter and transgene activities. Cancer Gene Therapy (2005) 12, 935-946.

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p53 Mutations in Human Cancers

Cited by 7,225 publications

References 70 publications

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

p53, Ki-67, and serum alpha feto-protein as predictors of hepatocellular carcinoma recurrence in liver transplant patients

A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition

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