p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding

Midgley, Carol A.; Lane, David P.

doi:10.1038/sj.onc.1201459

Cited by 285 publications

(213 citation statements)

References 31 publications

(40 reference statements)

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“…It might partially depend on the inefficient degradation exerted by the E3 ubiquitin ligase Mdm2, whose gene is a direct transcriptional target of wt-p53. Consequently, its activation is impaired in cells carrying mutant p53 proteins (Haupt et al, 1997;Kubbutat et al, 1997;Midgley and Lane, 1997;Bushmann et al, 2000;Strano and Blandino, 2003;Lain and Lane, 2005). Recent evidence derived from p53 knock-in mice have shown that mutant p53 proteins are unstable in normal tissues (Lang et al, 2004;Olive et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Mutant p53: an oncogenic transcription factor

Strano¹,

Dell’Orso²,

Agostino³

et al. 2007

Oncogene

243

184

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Inactivation of tumor-suppressor genes is one of the key hallmarks of a tumor. Unlike other tumor-suppressor genes, p53 is inactivated by missense mutations in half of all human cancers. It has become increasingly clear that the resulting mutant p53 proteins do not represent only the mere loss of wild-type p53 tumor suppressor activity, but gain new oncogenic properties favoring the insurgence, the maintenance, the spreading and the chemoresistance of malignant tumors. The actual challenge is the fine deciphering of the molecular mechanisms underlying the gain of function of mutant p53 proteins. In this review, we will focus mainly on the transcriptional activity of mutant p53 proteins as one of the potential molecular mechanisms. To date, the related knowledge is still quite scarce and many of the raised questions of this review are yet unanswered.

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Section: Introductionmentioning

confidence: 99%

Mutant p53: an oncogenic transcription factor

Strano¹,

Dell’Orso²,

Agostino³

et al. 2007

Oncogene

243

184

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“…MDM2 plays a central role in cancer development and progression, mainly by antagonizing the p53 tumor suppressor activity. Binding of MDM2 to p53 inhibits its transcriptional activity and targets p53 for ubiquitin-dependent proteolysis (Midgley and Lane, 1997;Piette et al, 1997). In response to cellular stress, the ability of MDM2 to bind p53 is blocked or altered in a manner that prevents MDM2-mediated degradation.…”

Section: Introductionmentioning

confidence: 99%

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

et al. 2006

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MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53À/À cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wildtype E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73a and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.

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“…In normal cells p53 protein has a very short half-life but, as mutant p53 protein is resistant to mdm-2± ubiquitin-mediated proteolysis, it accumulates within the cell 95 . This feature has been exploited clinically to identify p53 mutations indirectly by immunohistochemical detection of the protein 96 .…”

Section: P53mentioning

confidence: 99%

The colorectal adenoma–carcinoma sequence

Leslie

Carey

Pratt

et al. 2002

British Journal of Surgery

589

448

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Background: It is widely accepted that the adenoma±carcinoma sequence represents the process by which most, if not all, colorectal cancers arise. The evidence supporting this hypothesis has increased rapidly in recent years and the purpose of this article is to review this evidence critically and highlight its clinical signi®cance.Methods: Medline searches were used to identify recent key articles relating to the adenoma±carcinoma sequence. Further pertinent articles were obtained by manual scanning of the reference lists of identi®ed papers.Results: The evidence supporting the adenoma±carcinoma sequence can be classi®ed as epidemiological, clinicopathological and genetic. The most recent and largest body of data relates to molecular genetic events and their cellular effects; however, many other approaches, such as cytogenetics, molecular cytogenetics and cytometry, have also yielded valuable information.Conclusion: Recent work continues to support the adenoma±carcinoma sequence, but there is a paucity of data on the interrelationship between different genetic mutations and on the relationship between molecular and other types of genetic abnormalities. The clinical utility of the observations described has yet to be fully realized and global genetic analysis of colorectal tumours may prove to be central in rational adenoma management. IntroductionColorectal cancer is the second leading cause of cancerrelated death in the Western world; in the UK there are currently around 30 000 new cases per annum and 17 000 related deaths 1 . In recent years our understanding of the cellular and molecular events underlying the development of colorectal cancer has improved immeasurably but, despite this and advances in surgery, radiotherapy and chemotherapy, the average 5-year survival rate remains around 40 per cent 1 . One of the most important fundamental concepts in colorectal cancer to emerge in recent years has been the adenoma±carcinoma sequence, a term that describes the stepwise progression from normal to dysplastic epithelium to carcinoma associated with the accumulation of multiple clonally selected genetic alterations. This concept not only provides an excellent model to study the genesis of invasive cancer, but also affords a means of preventing colorectal cancer by endoscopic removal of precursor lesions.The appropriate management of individuals with precursor adenomatous polyps (adenomas) is of the utmost importance. It is known that after removal of such polyps 30±35 per cent of patients will have further adenomas detected at 3±4 years 2±4 and this has led to a policy of endoscopic surveillance for all adenoma-bearers 5 . However, given that approximately 40 per cent of the Western population will develop adenomas 6±8 and only 3 per cent will go on to suffer from colorectal cancer, it is clear that only a small proportion of adenomas progress to malignancy. Unfortunately, there are no reliable criteria available that can predict adenoma progression or recurrence, and the important questions of which individuals...

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p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding

Cited by 285 publications

References 31 publications

Mutant p53: an oncogenic transcription factor

Mutant p53: an oncogenic transcription factor

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

The colorectal adenoma–carcinoma sequence

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