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. 2006 May 30;103(22):8435-40.
doi: 10.1073/pnas.0602477103. Epub 2006 May 19.

p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors

William M Keyes  1 , Hannes Vogel, Maranke I Koster, Xuecui Guo, Yi Qi, Kristin M Petherbridge, Dennis R Roop, Allan Bradley, Alea A Mills
Affiliations

VSports在线直播 - p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors

William M Keyes et al. Proc Natl Acad Sci U S A. .

Abstract

Homology between p63 and p53 has suggested that these proteins might function similarly VSports手机版. However, the majority of data from human tumors have not supported a similar role for p63 in tumor suppression. To investigate this issue, we studied spontaneous tumorigenesis in p63+/- mice in both WT and p53-compromised backgrounds. We found that p63+/- mice were not tumor prone and mice heterozygous for both p63 and p53 had fewer tumors than p53+/- mice. The rare tumors that developed in mice with compromised p63 were also distinct from those of p53+/- mice. Furthermore, p63+/- mice were not prone to chemically induced tumorigenesis, and p63 expression was maintained in carcinomas. These findings demonstrate that, in agreement with data from human tumors, p63 plays a markedly different biological role in cancer than p53. .

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Conflict of interest statement (VSports在线直播)

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
p63 mouse models. (A) Schematic diagram of p63 with exons (rectangles) encoding the transactivating domain (blue), DBD (red), oligomerization domain (green), and sterile α motif (light gray) (GenBank accession no. AF533892). In contrast to previous reports the last exon of the γ isoform, exon 10′ (previously referred to as exon 15) is located between exons 10 and 11, which is also the case for human p63 (data not shown). (B) Structure of the previously generated p63Brdm1 and p63Brdm2 null alleles is shown (9). (C) Genotyping by Southern blot analysis identifies endogenous (E) and targeted (T) alleles for both p63 and p53. P denotes the p53 pseudogene.
Fig. 2.
Fig. 2.
Spontaneous tumor incidence is reduced by p63 heterozygosity. (A) The percentage of tumor-free WT, p63+/−, p53+/−, p63+/−;p53+/−, p53−/−, and p63+/−;p53−/− mice is shown. (B) Tumor incidence at 115 weeks is dramatically reduced in mice haploid for p63. The numbers of mice subjected to detailed histopathology were: p63+/+, 74; p63+/−, 104; p53+/−, 225; p63+/−;p53+/−, 47; p53−/−, 78; and p63+/−;p53−/−, 28. (C) Tumor onset depicted by using the Kaplan–Meier format. Note that even though overall tumor onset of p63+/− and p63+/+ cohorts appears similar when nontumor deaths are excluded, p63+/− mice develop significantly fewer tumors than WT mice. In addition, tumor onset is significantly delayed in mice heterozygous for both p63 and p53 relative to p53+/− mice.
Fig. 3.
Fig. 3.
Tumors from p63 mice do not exhibit LOH and retain expression of p63. (A) LOH analysis indicates that the p53 locus is frequently lost in tumors of p63+/−;p53+/− mice, whereas both p63 and p53 WT alleles are retained in tumors of p63+/− mice. Endogenous (E) and targeted (T) alleles for both p63 and p53 are shown. P denotes the p53 pseudogene. (B) Tumors were analyzed for expression of GAPDH and p63 by RT-PCR using primers common to all p63 transcripts. In addition, transcripts encoding TAp63 and ΔNp63 isoforms were detectable in all tumors analyzed. N, nonneoplastic; S, sarcoma; L, lymphoma; C, carcinoma; O, other. Controls: d, water; +, positive control (cDNA library was used for GAPDH and p63; plasmids containing cDNAs for either TAp63 or ΔNp63 isoforms were used as positive controls for specific transcript classes); −, negative controls (plasmids containing cDNA encoding the opposite p63 isoform). Total RNA was prepared from: sp, spleen; li, liver; t, tumor; ln, lymph node; ∗ indicates malignancy.
Fig. 4.
Fig. 4.
Histopathology of lymphomas. Tumors of p53-compromised mice have marked cytological atypia and a high mitotic rate, similar to some lymphomas (T) from p63+/− mice; other lesions were nonneoplastic (N) lymphoid proliferations. Lymphomas that developed in p63+/−;p53+/− mice had a large number of mitotic figures and apoptotic cells. (Scale bar: 100 μm.)
Fig. 5.
Fig. 5.
Genomic instability is not increased in lymphomas of p63-compromised mice. Flow cytometry indicates that p53+/− tumors are aneuploid (A), whereas both tumors (T) and nonneoplastic lesions (N) from p63+/− mice are diploid (D). In contrast, tumors from p63+/−;p53−/− mice are aneuploid.
Fig. 6.
Fig. 6.
p63+/− mice are not predisposed to chemically induced skin tumors. p63+/+ and p63+/− mice treated with dimethylbenz[a]anthracene/tetradecanoyl-phorbol-13-acetate were monitored for tumorigenesis. (A–C) The percentage of tumor-bearing mice (A), average number of tumors per mouse (B), and percentage of mice with carcinomas (C) indicate that p63+/− mice are not predisposed to skin tumors. (D) Papillomas and SCCs retain p63 expression, indicating that p63 does not function as a tumor suppressor in this setting. Shown is expression of K14 (red) and p63 (green).
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References

    1. Murray-Zmijewski F., Lane D. P., Bourdon J. C. Cell Death Differ. 2006 in press. - PubMed
    1. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. Science. 1991;253:49–53. - PubMed
    1. Wu G., Nomoto S., Hoque M. O., Dracheva T., Osada M., Lee C. C., Dong S. M., Guo Z., Benoit N., Cohen Y., et al. Cancer Res. 2003;63:2351–2357. - "VSports最新版本" PubMed
    1. Yang A., Kaghad M., Wang Y., Gillett E., Fleming M. D., Dotsch V., Andrews N. C., Caput D., McKeon F. Mol. Cell. 1998;2:305–316. - PubMed
    1. Moll U. M., Slade N. Mol. Cancer Res. 2004;2:371–386. - "VSports在线直播" PubMed

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