The p53 Tumor Suppressor Causes Congenital Malformations in <i>Rpl24</i>-Deficient Mice and Promotes Their Survival

Barkić, Martina; Crnomarković, Slađana; Grabušić, Kristina; Bogetić, Ivana; Panić, Linda; Tamarut, Sanda; Cokarić, Maja; Jeric, Ines; Vidak, Sandra; Volarević, Siniša

doi:10.1128/mcb.01588-08

Cited by 93 publications

(88 citation statements)

References 57 publications

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“…S7E), which were reported in the Bst mouse associated with p53 activation (22,23). Despite the elevated levels of p21, little differences in Pcna mRNA expression and Ki67 staining were observed between Mdm2…”

Section: Mdm4mentioning

confidence: 90%

p53 pathway is involved in cell competition during mouse embryogenesis

Zhang

Xie

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The function of tumor suppressor p53 has been under intense investigation. Acute stresses such as DNA damage are able to trigger a high level of p53 activity, leading to cell cycle arrest or apoptosis. In contrast, the cellular response of mild p53 activity induced by low-level stress in vivo remains largely unexplored. Murine double minute (MDM)2 and MDM4 are two major negative regulators of p53. Here, we used the strategy of haploinsufficiency of Mdm2 and Mdm4 to induce mild p53 activation in vivo and found that Mdm2+/−Mdm4+/− double-heterozygous mice exhibited normal embryogenesis. However, closer examination demonstrated that the Mdm2+/−Mdm4+/− cells exhibited a growth disadvantage and were outcompeted during development in genetic mosaic embryos that contained wild-type cells. Further study indicated the out-competition phenotype was dependent on the levels of p53. These observations revealed that cells with mild p53 activation were less fit and exhibited altered fates in a heterotypic environment, resembling the cell competition phenomenon first uncovered in Drosophila. By marking unfit cells for elimination, p53 may exert its physiological role to ensure organ and animal fitness.

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Section: Mdm4mentioning

confidence: 90%

p53 pathway is involved in cell competition during mouse embryogenesis

Zhang

Xie

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The Belly Spot and Tail mouse is caused by a partial deletion in Rpl24 leading to congenital malformations of the eye and skeleton, in addition to the skin hyperpigmentation observed in other RP-deficient models (Tang et al, 1999;Oliver et al, 2004). These defects are caused, in part, by elevated p53 levels, which contribute to the overall survival of the mice (Barkic et al, 2009). The selective impairment of specific RPs in mouse models is sufficient to suggest the existence of an in vivo RP-Mdm2-p53 pathway, but further studies investigating the dependence of RP imbalances on this pathway and the specific defects associated with individual loss of RPs are warranted.…”

Section: Rp Imbalances Activate P53mentioning

confidence: 99%

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

2010

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“…RNAi, plasmids and transfection reagents Select stealth RNAi (Invitrogen, Carlsbad, UK) targeted against catalytic subunit of RNA Polymerase I (POLR1A) and siRNA against rpL11 (described by Barkic´et al (2009), target sequence 1) were used, whereas stealth RNAi negative control (Invitrogen) or a scrambled sequence siRNA was used to transfect controls, respectively. Cells were transfected with lipofectamine RNAiMAX (Invitrogen) in opti-MEM medium (Invitrogen), accordingly to manufacturer's procedures.…”

Section: Animalsmentioning

confidence: 99%

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

et al. 2011

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Data on the relationship between ribosome biogenesis and p53 function indicate that the tumour suppressor can be activated by either nucleolar disruption or ribosomal protein defects. However, there is increasing evidence that the induction of p53 does not always require these severe cellular changes, and data are still lacking on a possible role of ribosome biogenesis in the downregulation of p53. Here, we studied the effect of the up-and downregulation of the rRNA transcription rate on p53 induction in mammalian cells. We found that a downregulation of rRNA synthesis, induced by silencing the POLR1A gene coding for the RNA polymerase I catalytic subunit, stabilised p53 without altering the nucleolar integrity in human cancer cells. p53 stabilisation was due to the inactivation of the MDM2-mediated p53 degradation by the binding of ribosomal proteins no longer used for ribosome building. p53 stabilisation did not occur when rRNA synthesis downregulation was associated with a contemporary reduction of protein synthesis. Furthermore, we demonstrated that in three different experimental models characterised by an upregulation of rRNA synthesis, cancer cells treated with insulin or exposed to the insulin-like growth factor 1, rat liver stimulated by cortisol and regenerating rat liver after partial hepatectomy, the p53 protein level was reduced due to a lowered ribosomal protein availability for MDM2 binding. It is worth noting that the upregulation of rRNA synthesis was responsible for a decreased p53-mediated response to cytotoxic stresses. These findings demonstrated that the balance between rRNA and ribosomal protein synthesis controls the function of p53 in mammalian cells, that p53 can be induced without the occurrence of severe changes of the cellular components controlling ribosome biogenesis, and that conditions characterised by an upregulated rRNA synthesis are associated with a reduced p53 response.

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The p53 Tumor Suppressor Causes Congenital Malformations in Rpl24-Deficient Mice and Promotes Their Survival

Cited by 93 publications

References 57 publications

p53 pathway is involved in cell competition during mouse embryogenesis

p53 pathway is involved in cell competition during mouse embryogenesis

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

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