p53 in embryonic development: maintaining a fine balance

Choi, Jong Min; Donehower, Larry A.

doi:10.1007/s000180050268

Cited by 132 publications

(82 citation statements)

References 56 publications

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“…The function of p53 in development and its importance in the control of differentiation processes have been previously established with some discrepancies; some studies suggest that p53 facil-itates cell differentiation whereas in others it seems to be suppressive [51,52]. Our study showed that the expression of p53 protein in all cell types (SC, uMSC, dMSC, uASC and dASC) from the three different age donors did not differ significantly.…”

Section: Discussionmentioning

confidence: 42%

Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages

Mantovani

Raimondo

Haneef

et al. 2012

Experimental Cell Research

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Section: Discussionmentioning

confidence: 42%

Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages

Mantovani

Raimondo

Haneef

et al. 2012

Experimental Cell Research

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“…Because the G allele of SNP309 has a lower apoptotic frequency than the T allele in some cell types in culture (11,13), it is tempting to speculate that the presence of the G allele could compensate for higher apoptotic frequencies brought about by the p53-Arg isoform as populations move to northern Asia and Europe. A well regulated p53 pathway has been shown in many organisms to be crucial not only for tumor suppression but also for proper embryonic development (34,35); therefore, selection pressure on the p53 pathway could be possible. In fact, the p53 pathway also responds to inflammation, raising the possibility that infectious diseases could play a role in the selection of p53 pathway SNPs, like MDM2 SNP309 and codon 72.…”

Section: Discussionmentioning

confidence: 99%

Haplotype structure and selection of the MDM2 oncogene in humans

Atwal

Bond

Metsuyanim³

et al. 2007

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

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The MDM2 protein is an ubiquitin ligase that plays a critical role in regulating the levels and activity of the p53 protein, which is a central tumor suppressor. A SNP in the human MDM2 gene (SNP309 T/G) occurs at frequencies dependent on demographic history and has been shown to have important differential effects on the activity of the MDM2 and p53 proteins and to associate with altered risk for the development of several cancers. In this report, the haplotype structure of the MDM2 gene is determined by using 14 different SNPs across the gene from three different population samples: Caucasians, African Americans, and the Ashkenazi Jewish ethnic group. The results presented in this report indicate that there is a substantially reduced variability of the deleterious SNP309 G allele haplotype in all three populations studied, whereas multiple common T allele haplotypes were found in all three populations. This observation, coupled with the relatively high frequency of the G allele haplotype in both and Caucasian and Ashkenazi Jewish population data sets, suggests that this haplotype could have undergone a recent positive selection sweep. An entropy-based selection test is presented that explicitly takes into account the correlations between different SNPs, and the analysis of MDM2 reveals a significant departure from the standard assumptions of selective neutrality.cancer ͉ p53 ͉ population genetics ͉ SNP ͉ entropy I n response to a wide variety of stresses, such as DNA damage or oncogene activation, the p53 tumor suppressor protein is activated and initiates a transcriptional program leading to cell cycle arrest, cell senescence or apoptosis (1). This eliminates clones of cells that have acquired mutations, which arise at a high frequency when DNA replication or the cell cycle proceeds under stress. When the p53 gene is mutated in either the germ line or in a somatic cell, many types of cancers can arise (2). The p53 protein is regulated by a ubiquitin ligase, the MDM2 protein, which binds to p53, blocking its function as a transcription factor, and polyubiquitinates the p53 protein sending it to the proteiosome for degradation (3). The MDM2 gene in turn is positively regulated by p53-mediated transcription, setting up an autoregulatory loop that keeps both proteins at moderate levels. Stress responses perturb this feedback loop, which leads to the initiation of p53-dependent apoptosis.Functional SNPs in the human genome have been identified in both the p53 and the MDM2 genes (4). In the p53 gene, a SNP (codon 72) results in the change of a proline residue to an arginine at codon 72 of the p53 protein (p53-Pro and p53-Arg, respectively). Multiple groups have shown that p53-Pro is weaker than p53-Arg in its ability to both suppress cellular transformation and induce apoptosis in cell culture (5-8), and can associate with an earlier onset of tumor formation and a poorer tumor response to chemotherapy in humans (7, 9, 10). In the MDM2 gene, a SNP (SNP309) results in a nucleotide change from the wild-type thymine (T...

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“…These include cell cycle exit, which involves the activation of tumour suppressors p53 (Miller et al, 2003) and pRb (Slack et al, 1993;Slack et al, 1998). Both of them are important at various times of brain development (reviewed by Choi and Donehower, 1999), and their deficiency frequently results in brain anomalies (Armstrong et al, 1995) or embryonic death (Macleod et al, 1996;Slack et al, 1998). The role of pRb family members in terminal differentiation of neurons seems to be complex, as pRb has both cell cycle (cell-autonomous) and differentiation controlling functions (noncell-autonomous) (Liu et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

E6/E7 oncogenes increase and tumor suppressors decrease the proportion of self-renewing neural progenitor cells

et al. 2006

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Many if not most tissues need a controlled number of stem cells to maintain normal function. Cancer can be seen as a process of disturbed tissue homeostasis, in which too many cells have or acquire too primitive identity. Here we measured how oncogenes and tumour suppressors affect the differentiation capacity, proportion and characteristics of progenitor cells in a model tissue. Neural progenitor cells (NPCs) were exposed to human papilloma virus E6, E7 or E6/E7 oncogenes, which degrade tumour suppressors p53 and pRb family members, respectively. E6/E7-expressing or p53À/À NPCs were able to differentiate, but simultaneously retained high capacity for self-renewal, proliferation, ability to remain multipotent in conditions promoting differentiation and showed delayed cell cycle exit. These functions were mediated through p53 and pRb family, and involved MEK-ERK signalling. Decreased amount of p53 increased selfrenewal and proliferation, whereas pRb affected only proliferation. Our results suggest that the oncogenes increase whereas p53 and pRb family tumour suppressors decrease the number and proportion of progenitor cells. These findings provide one explanation how oncogenes and tumour suppressors control tissue homeostasis and highlight their importance in stem cell self-renewal, linked both to cancer and life-long tissue turnover.

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p53 in embryonic development: maintaining a fine balance

Cited by 132 publications

References 56 publications

Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages

Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages

Haplotype structure and selection of the MDM2 oncogene in humans

E6/E7 oncogenes increase and tumor suppressors decrease the proportion of self-renewing neural progenitor cells

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