Mice Lacking the p53/p63 Target Gene <i>Perp</i> Are Resistant to Papilloma Development

Marques, Michelle R.; Horner, Jennifer S.; Ihrie, Rebecca A.; Bronson, Roderick T.; Attardi, Laura D.

doi:10.1158/0008-5472.can-05-0366

Cited by 26 publications

(24 citation statements)

References 30 publications

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“…41,42 p53 is a known regulator of adhesion molecule expression such as E-cadherin, 43 as well as of adhesion-associated molecules such as Perp. 44,45 Comparing adhesion and migration differences in cells from p53-mutant ducts, although challenging, will offer much insight into mechanisms of UB outgrowth.…”

Section: Discussionmentioning

confidence: 99%

p53 Regulates Metanephric Development

Saifudeen

Dipp

Stefkova

et al. 2009

Journal of the American Society of Nephrology

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p53 is best known as a tumor suppressor that regulates cell-cycle, differentiation, and apoptosis pathways, but its potential role in embryonic development and organogenesis remains controversial. Here, p53Ϫ/Ϫ embryos bred on C57Bl6 background exhibited a spectrum of congenital abnormalities of the kidney and urinary tract, including ureteric bud (UB) ectopia, double ureters/collecting systems, delayed primary branching of the UB, and hypoplastic metanephroi. We observed ectopic UB outgrowth from the Wolffian duct (WD) in one third of p53 Ϫ/Ϫ embryos. The prevalence of duplex was higher in embryos than in neonates, and ex vivo organ culture suggested that ectopic ureters can regress over time, leaving behind a dysplastic pole ("segmental dysgenesis"). Transgenic expression of dominant negative p53 or conditional inactivation of p53 in the UB but not in the metanephric mesenchyme lineage recapitulated the duplex phenotype. Mechanistically, p53 inactivation in the WD associated with enhanced sensitivity to glial cell line-derived neurotrophic factor (GDNF)-induced ectopic budding and potentiated phosphatidylinositol-3 kinase activation by GDNF in UB cells. Unlike several other models of UB ectopia, hypersensitivity of p53 Ϫ/Ϫ WD to GDNF is not accompanied by reduced Sprouty-1 or anterior expansion of the GDNF domain. In summary, our data lend support for a restrictive role for p53 activity in UB outgrowth from the WD. Organogenesis is dependent on a multitude of growth factors, signaling molecules, and transcription factors that temporally and spatially define a developmental program. Metanephric development is dependent on formation of the Wolffian duct (WD) and the adjacent metanephric mesenchyme (MM) from the intermediate mesoderm. In mice, the ureteric bud (UB) develops at embryonic day 10.5 (E10.5) from the caudal end of the WD. Inductive interactions between the UB and the MM ensure cell survival and subsequent onset of metanephrogenesis. Emergence of the UB from a specific site in the WD adjacent to the MM is controlled by the glial cell line-derived neurotrophic factor (GDNF)-cRet signaling pathway. 1-6 GDNF is a growth factor that is secreted by the MM and binds to its receptor c-Ret and co-receptor GFR␣1 that are expressed along the WD and UB tips. Stimulation of the GDNF-cRet pathway results in cell proliferation and chemotaxis. 7,8 After the initial broad distribution of the GDNF field along the posterior half of the WD, the GDNF expression domain is progressively restricted to the caudal end of the WD in the immediate vicinity of the site of UB outgrowth 9 -11 ; however, the potential for bud emergence remains along the length of the WD, which continues to express the c-Ret/GFR␣1 receptor/co-receptor. Evidence from mutant mouse models and metanephric organ culture implicates impaired restriction of the GDNF field and the GDNF/c-Ret signaling pathway in ureter duplica-

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Section: Discussionmentioning

confidence: 99%

p53 Regulates Metanephric Development

Saifudeen

Dipp

Stefkova

et al. 2009

Journal of the American Society of Nephrology

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“…Nevertheless, studying the role of PERP during development and in adult tissues is limited by the lethality of PERP-KO mice postnatally [10 -14 days] (16,25). The embryonic lethality of PERP-KO mice is partly attributed to a lack of stable assembly of desmosomal adhesive complexes in the skin, resulting in blistering of stratified epithelia, thus compromising epithelial integrity.…”

Section: Discussionmentioning

confidence: 99%

PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia

Singaravelu¹,

Devalaraja-Narashimha²,

Lastovica³

et al. 2009

American Journal of Physiology-Renal Physiology

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“…These data support our previous observations showing that Perp ablation in the skin does not enhance, and in fact decreases, the predisposition of mice to tumor development in a two-step carcinogenesis protocol, suggesting that Perp, and intact desmosome function, are required for tumor initiation in the skin. 9 Together, these findings highlight the important role for Perp in proper homeostasis and function of the ectoderm and its derivatives, rather than in suppression of tumor initiation.…”

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confidence: 85%