Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice

Hingorani, Sunil R.; Wang, Lifu; Multani, Asha S.; Combs, Chelsea; Deramaudt, Thérèse B.; Hruban, Ralph H.; Rustgi, Anil K.; Chang, Sandy; Tuveson, David A.

doi:10.1016/j.ccr.2005.04.023

Cited by 2,252 publications

(2,530 citation statements)

References 49 publications

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“…Our findings are consistent with observations of mutant p53 GOF in mouse models where expression of the mouse R172H mutant (equivalent to human R175H) results in tumours showing centrosome amplification and an associated aneuploidy (Murphy et al, 2000;Hingorani et al, 2005;Caulin et al, 2007). However, these previous reports are confounded as they use a K-Ras G12D mutation as an initiating oncogenic event (Hingorani et al, 2005;Caulin et al, 2007). Our data show that mutant p53 alone is sufficient to drive the observed GOF phenotype.…”

Section: Input Igg Pab1620supporting

confidence: 91%

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

et al. 2011

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Mutations of p53 in cancer can result in a gain of function associated with tumour progression and metastasis. We show that inducible expression of several p53 'hotspot' mutants promote a range of centrosome abnormalities, including centrosome amplification, increased centrosome size and loss of cohesion, which lead to mitotic defects and multinucleation. These mutant p53-expressing cells also show a change in morphology and enhanced invasive capabilities. Consequently, we sought for a means to specifically target the function of mutant p53 in cancer cells. This study has identified ANKRD11 as a key regulator of the oncogenic potential of mutant p53. Loss of ANKRD11 expression with p53 mutation defines breast cancer patients with poor prognosis. ANKRD11 alleviates the mitotic defects driven by mutant p53 and suppresses mutant p53-mediated mesenchymal-like transformation and invasion. Mechanistically, we show that ANKRD11 restores a native conformation to the mutant p53 protein and causes dissociation of the mutant p53-p63 complex. This represents the first evidence of an endogenous protein with the capacity to suppress the oncogenic properties of mutant p53.

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Section: Input Igg Pab1620supporting

confidence: 91%

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

et al. 2011

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“…It is now becoming more generally apparent that many mouse tissues designed to express this single K-ras allele do not exhibit much if any ERK and AKT activation (Kim et al, 2005). In contrast, when these mice are crossed to other tumor-prone strains to generate animals with compound mutations, the resulting tumors do exhibit activation of Ras effectors, implying that this suppression is somehow alleviated in the course of tumor development and/or progression (Dinulescu et al, 2005;Hingorani et al, 2005).…”

Section: Mechanisms Of Oncogene-induced Senescence S Courtois-cox Et Almentioning

confidence: 99%

Many roads lead to oncogene-induced senescence

2008

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“…Cooperative mutations in proto-oncogenes and tumor suppressor genes occur in many forms of cancer. 27,28 The model of cooperative mutations causing a reduction in Ikaros activity and an increase in Notch1 activation fits this paradigm in the genesis of T-ALL. 30,44 However, most Notch1 mutations found in TL do not generate signals of sufficient strength to initiate leukemia development and require other leukemogenic factors.…”

Section: Discussionmentioning

confidence: 79%

Ikaros is a critical target during simultaneous exposure to X‐rays and N‐ethyl‐N‐nitrosourea in mouse T‐cell lymphomagenesis

Hirano

Kakinuma

Amasaki³

et al. 2012

Intl Journal of Cancer

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Cancer risk associated with radiation exposure is considered the result of concurrent exposure to other natural and manmade carcinogens. Available data on the molecular characteristics of cancer after simultaneous exposure to radiation and chemicals are insufficient. In our study, we used a mouse thymic lymphoma (TL) model that was synergistically induced by simultaneous exposure to X-rays and N-ethyl-N-nitrosourea (ENU) at subcarcinogenic doses and analyzed the mutation frequency and spectrum of the TL-associated genes Ikaros, Notch1, p53 and Kras. We found that the point mutation frequency in Ikaros was significantly increased to 47% for simultaneous exposure compared to 13 and 0% for X-ray and ENU exposure alone, respectively. These mutations were mostly G:C > A:T at non-CpG sites and T:A > C:G, both of which are characteristic of ENU mutagenesis. About half of the point mutations were accompanied by loss of heterozygosity (LOH), typical of X-irradiation. The remaining half did not include LOH, which suggests that they were dominant-negative mutations. In Notch1, the frequency of abnormalities was high (>58%) regardless of the treatment, suggesting that Notch1 aberration may be important for T-cell lymphomagenesis. The p53 and Kras mutation frequencies were low for all treatments (<23%). Importantly, the frequency of TLs containing mutations in multiple genes, especially both Ikaros and Notch1, increased after simultaneous exposure. Thus, after simultaneous exposure, Ikaros is a critical target and is inactivated by ENU-induced point mutations and/or X-ray-induced LOH in T-cell lymphomagenesis. Furthermore, concomitant alterations of multiple tumor-associated genes may contribute to enhanced lymphomagenesis after simultaneous exposure.A multitude of natural and manmade chemicals with cancerinitiating and cancer-promoting potential are present in the environment. Many human cancers show considerable dependence on lifestyle, such as the use of tobacco, and dietary factors. 1 Moreover, radiation carcinogenesis in humans is considered to result from the combined effect of radiation exposure and environmental carcinogens. There have been many attempts to estimate the risk of such combined exposure in animal and cell culture models. 2,3 There is, however, almost no information about the molecular mechanism that leads to carcinogenesis following combined exposure. Murine thymic lymphoma (TL) can be reproducibly induced by exposure to ionizing radiation and chemical carcinogens such as N-ethyl-N-nitrosourea (ENU), and this model is considered useful in the search for and Key words: simultaneous exposure, X-ray, N-ethyl-N-nitrosourea, thymic lymphoma, Ikaros Abbreviations: B-ALL: B-cell acute lymphoblastic leukemia; ENU: N-ethyl-N-nitrosourea; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; gpt: guanine phosphoribosyltransferase; HD: heterodimerization; Hes1: hairy enhancer of split-1; LOH: loss of heterozygosity; Mgmt: O 6 -methylguanine-DNA methyltransferase; PEST: polypeptide rich in proline, glutamate, serine and...

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Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice

Cited by 2,252 publications

References 49 publications

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Many roads lead to oncogene-induced senescence

Ikaros is a critical target during simultaneous exposure to X‐rays and N‐ethyl‐N‐nitrosourea in mouse T‐cell lymphomagenesis

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