Knockin mice expressing a chimeric p53 protein reveal mechanistic differences in how p53 triggers apoptosis and senescence

Meade, Kristin E.; Pathak, Navneeta; Marques, Michelle R.; Attardi, Laura D.

doi:10.1073/pnas.0706764105

Cited by 33 publications

(21 citation statements)

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“…Tumors were not observed in the ⌬40p53 mice 9 and not reported for another N-terminally truncated p53 mouse, 28 but mice containing small deletions or point mutations in the N-terminus of p53 are tumor prone, [29][30][31] predominantly developing B-cell tumors. In these cases, the tumors appeared much later than in ⌬122p53 mice and are the result of impaired p53 function.…”

Section: Discussionmentioning

confidence: 99%

Hyperproliferation, cancer, and inflammation in mice expressing a Δ133p53-like isoform

Slatter

Hung

Campbell

et al. 2011

Blood

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The p53 protein is a pivotal tumor suppressor that is frequently mutated in many human cancers, although precisely how p53 prevents tumors is still unclear. To add to its complexity, several isoforms of human p53 have now been reported. The ⌬133p53 isoform is generated from an alternative transcription initiation site in intron 4 of the p53 gene (Tp53) and lacks the N-terminus. Elevated levels of ⌬133p53 have been observed in a variety of tumors. To explore the functions of ⌬133p53, we created a mouse expressing an N-terminal deletion mutant of p53 (⌬122p53) that corresponds to ⌬133p53. ⌬122p53 mice show decreased survival and a different and more aggressive tumor spectrum compared with p53 null mice, implying that ⌬122p53 is a dominant oncogene. Consistent with this, ⌬122p53 also confers a marked proliferative advantage on cells and reduced apoptosis. In addition to tumor development, ⌬122p53 mice show a profound proinflammatory phenotype having increased serum concentrations of interleukin-6 and other proinflammatory cytokines and lymphocyte aggregates in the lung and liver as well as other pathologies. Based on these observations, we propose that human ⌬133p53 also functions to promote cell proliferation and inflammation, one or both of which contribute to tumor development. (Blood. 2011;117(19): 5166-5177) Introduction p53 is most important for preventing cancers. We know this because mice deleted for the p53 gene (Trp53) are highly tumor prone 1 ; in humans, Li-Fraumeni syndrome, characterized by multiple tumor phenotypes, is the result of germline inherited mutations in the p53 gene (Tp53) 2 ; and most common human cancers contain mutations in Tp53 (www.p53.iarc.fr), generally rendering the protein functionally impaired. Ten isoforms of human p53 have been reported that are generated by the use of alternative translation initiation sites, splicing, or alternative promoters. [3][4][5][6][7][8][9] Two p53 isoforms (⌬40p53 and ⌬133p53) lack the N-terminus of p53, whereas 4 others (⌬40p53␤, ⌬40p53␥, ⌬133p53␤, and ⌬133p53␥) also lack part of the C-terminus beyond codon 331. In addition, 3 more isoforms have recently been described (⌬160p53, ⌬160p53␤, ⌬160p53␥) that use an alternative start codon at position 161 in the transcript for the ⌬133p53 isoform family. 8 The isoforms are generally expressed in a variable and to some extent tissue specific manner, although the ⌬133p53 isoform appears to be ubiquitous. 5 Aberrant expression of the ⌬133p53 isoforms occurs in a variety of tumors, including breast, 5 head and neck, 10 acute myeloid leukemia, 11 melanoma, 12 colon cancer, 13 and ovarian cancer, 14 suggesting that ⌬133p53 contributes to tumor formation. In zebrafish, the homolog of ⌬133p53 (⌬113p53) attenuates p53-dependent apoptosis by activating the homolog (bcl2l) of the antiapoptotic protein Bcl-xl, 15 and knockdown of ⌬113p53 using silencing RNA induced p53-dependent apoptosis. In another study, overexpression of ⌬133p53 extended the life span of normal human fibroblasts by inhibiting replicative senescen...

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Section: Discussionmentioning

confidence: 99%

Hyperproliferation, cancer, and inflammation in mice expressing a Δ133p53-like isoform

Slatter

Hung

Campbell

et al. 2011

Blood

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“…Obligatory loss of transactivation function in senescence bypass-selected p53 mutants would support the findings from a recent study in knock-in mice harboring a chimeric p53 protein lacking motifs for nontransactivation-related functions. This elegant report demonstrated that p53-induced senescence of primary MEFs is dependent on the transactivation properties of p53 (52).…”

Section: Discussionmentioning

confidence: 99%

Wild-type and Hupki (Human p53 Knock-in) Murine Embryonic Fibroblasts

Whibley

Odell

Nedelko

et al. 2010

Journal of Biological Chemistry

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Research on cell senescence and immortalization of murine embryonic fibroblasts (MEFs) has revealed important clues about genetic control of senescence in humans. To investigate senescence and genetic alterations in the p53 pathway that lead to senescence bypass in culture, we compared the behavior of MEFs from wild-type mice with MEFs from Hupki mice, which harbor a humanized p53 gene. We found that humanizing the p53 gene in mice preserved major features of the MEF senescence/immortalization process. In both genotypes, a significant proportion of spontaneously arising cell lines had sustained either a p53 point mutation or p19/ARF biallelic deletion. The p53 mutations selected for during Hupki MEF immortalization have been found in human tumors and are classified in the yeast transactivation assay as transcriptionally defunct, suggesting that disabling this component of p53 activity is crucial in senescence bypass. Surprisingly, in spontaneously immortalized cell lines from both wild-type and Hupki MEFs, the predominant type of p53 mutation was a G to C transversion, rather than the G to T substitutions expected from the raised oxygen levels characteristic of standard culture conditions. Over half of the cell lines did not reveal evidence of p53 mutation or loss of p19/ ARF and retained a robust wild-type p53 response to DNA damage, supporting the inference from senescence bypass screens that alternative genetic routes to immortalization occur.Cellular senescence is an important defense against tumor development, but it also plays a role in aging and is a barrier to the successful reprogramming of somatic cells to pluripotency (1-3). Senescence may be triggered by a variety of events, including DNA damage, expression of oncogenes, telomere shortening, and derepression of the ARF locus (4). Although the evasion of senescence can have disastrous consequences for tumor chemotherapy (5, 6), blocking senescence has been the key to recent success in generating pluripotent stem cells from fibroblasts, bringing the promise of therapeutic use for pluripotent stem cells a step closer (7). Understanding the ways in which cells are able to bypass senescence is thus relevant to the causes and treatment of cancer at multiple levels.Mouse embryonic fibroblasts (MEFs) 2 are a classic model system for studying senescence. Early ground-breaking studies established the importance of inactivation of the p53/p19ARF pathway in the immortalization of MEFs (8 -11) More recently, high throughput screening methods have been used to investigate senescence rescue in MEFs, and these have shown that disturbances in other components of the p53/Rb/AKT suppressor networks may conspire to prevent permanent growth arrest (12-15).Immortalization of human cells in culture is more complex than for MEFs. Disruption of the p53/p14ARF pathway (which corresponds to mouse p53/p19ARF) remains essential, but in addition, disruption of the Rb/p16 arm of the tumor suppressor node is necessary, together with a halt in telomere attrition during replication (...

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“…Cite this article as Cold Spring Harb Perspect Biol 2009;00:a001883 of transactivation ( p53VP16), but lacking domains involved in transactivation-independent functions (i.e., transcriptional repression) (Johnson et al 2008). p53VP16 was able to robustly transactivate p53 targets involved both in apoptosis and senescence.…”

Section: Tumor Suppressive Functions Of P53mentioning

confidence: 99%