Temporal dissection of p53 function in vitro and in vivo

Christophorou, Maria A.; Martı́n-Zanca, Dionisio; Soucek, Laura; Lawlor, Elizabeth R.; Brown-Swigart, Lamorna; Verschuren, Emmy W.; Evan, Gérard I.

doi:10.1038/ng1572

Cited by 183 publications

(222 citation statements)

References 25 publications

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“…This correlates with the absence of p53-induced growth suppression in cultured cells derived from p53ER TAM KI mice upon 4-OHT treatment in vitro. However, restoration of p53 activity by 4-OHT in irradiated cells or in cells expressing oncogenic Ras leads to activation of p53 and its target genes, thus unleashing the p53 growth suppressor function (Christophorou et al, 2005). These results provide compelling evidence supporting the notion that oncogene expression is required for the functional activity of p53 in cells.…”

Section: Advantages Of Mutant P53 Rescue As a Therapeutic Strategymentioning

confidence: 65%

“…Finally, owing to constitutive stress signaling in tumor cells, for example oncogene activation, DNA damage and hypoxia, mutant p53 is probably already 'activated' by post-translational modifications and partner proteins, whereas p53 is latent in normal cells in the absence of stress (Figure 1). This notion is supported by studies of p53ER TAM knock-in (KI) mice (Christophorou et al, 2005). This model makes it possible to switch p53 on and off in tissues in vivo.…”

Section: Advantages Of Mutant P53 Rescue As a Therapeutic Strategymentioning

confidence: 87%

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Reactivation of mutant p53: molecular mechanisms and therapeutic potential

2007

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Section: Advantages Of Mutant P53 Rescue As a Therapeutic Strategymentioning

confidence: 65%

Section: Advantages Of Mutant P53 Rescue As a Therapeutic Strategymentioning

confidence: 87%

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

2007

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“…41 While it is known that p53 is modified after stress, the temporal requirement for p53 presence after different stresses has been largely unexplored. Recent work by Evan and co-workers 42 describes the generation of a knock-in mouse in which a p53-(ER) (p53-ER) fusion replaced the wild-type allele. Fusion of the ligand-binding domain of this modified version of the ER to a protein renders the protein activatable by synthetic, but not natural, forms of estrogen.…”

Section: Upstream Signaling To P53mentioning

confidence: 99%

“…This study analyzed the temporal requirement for p53 activation in response to stresses such as DNA damage. 42 The data suggest that the reaction of p53 to an acute stress such as DNA damage is highly dependent on p53 being present to receive an initial 'signal' from an upstream stress sensor, such as the ATM protein kinase; if functional p53 protein is absent directly after the stress, but is then activated via 4-OHT treatment at a later time, a p53 response will not be initiated. In contrast, the response of p53 to a more persistent stress, such as the activation of an oncogene, yields a different result.…”

Section: Upstream Signaling To P53mentioning

confidence: 99%

Dissecting p53 tumor suppressor function in vivo through the analysis of genetically modified mice

Attardi

2006

Cell Death Differ

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“…Previous studies have demonstrated a developmental role for p53 in several organisms including X. laevis (2,23,64,65,69), and the mouse (13,16,18,19,21,32,38,39,44,59). We recently reported that terminal nephron differentiation is accompanied by p53 phosphorylation and acetylation, protein stabilization, and enhanced DNA binding activity (54).…”

Section: The P53 Family Regulates Both Cell Cycle Progression and Termentioning

confidence: 99%

Transcriptional control of terminal nephron differentiation

El‐Dahr

Aboudehen

Saifudeen

2008

American Journal of Physiology-Renal Physiology

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entiation of epithelial cells into more specialized cell types is a critical step in organogenesis. Throughout the process of terminal differentiation, epithelial progenitors acquire or upregulate expression of renal function genes and cease to proliferate, while expression of embryonic genes is repressed. This exquisite coordination of gene expression is accomplished by signaling networks and transcription factors which couple the external environment with the new functional demands of the cell. While there has been much progress in understanding the early steps involved in renal epithelial cell differentiation, a major gap remains in our knowledge of the factors that control the steps of terminal differentiation. A number of signaling molecules and transcription factors have been recently implicated in determining segmental nephron identity and functional differentiation. While some of these factors (the p53 gene family, hepatocyte nuclear factor-1␤) promote the terminal epithelial differentiation fate, others (Notch, Brn-1, IRX, KLF4, and Foxi1) tend to regulate differentiation of specific nephron segments and individual cell types. This review summarizes current knowledge related to these transcription factors and discusses how diverse cellular signals are integrated to generate a transcriptional output during the process of terminal differentiation. Since these transcriptional processes are accompanied by profound changes in nuclear chromatin structure involving the genes responsible for creating and maintaining the differentiated cell phenotype, future studies should focus on identifying the nature of these epigenetic events and factors, how they are regulated temporally and spatially, and the chromatin environment they eventually reside in. transcription factors; kidney development; p53; gene expression TERMINAL DIFFERENTIATION IS a key biological process characterized by cell cycle arrest and acquisition of specialized functions by each cell type. The genetic programs that couple cellular growth to functional differentiation are a subject of intense investigation (78). There is increasing appreciation that although formation of adequate numbers of nephrons (i.e., renal mass) is critical for achieving optimal renal function capacity, the signals that determine how, when, and which renal epithelial cells should acquire a given functional phenotype are equally essential. Aberrant terminal differentiation is a hallmark of dysplasia, cyst formation, and cancer, and therapeutic interventions to promote differentiation and cell cycle arrest [e.g., EGF receptor (EGFR) antagonists and histone deacetylase inhibitors] are effective measures in some models of polycystic kidney disease and cancer (17,26,72,73). Therefore, identification of factors that couple cell cycle arrest with functional differentiation is of great clinical importance. Termination of Nephrogenesis and Differentiation are Dynamic and Coordinated ProcessesThe metanephric kidney is derived from the intermediate mesoderm at embryonic (E) day 10.5 (E...

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Temporal dissection of p53 function in vitro and in vivo

Cited by 183 publications

References 25 publications

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

Dissecting p53 tumor suppressor function in vivo through the analysis of genetically modified mice

Transcriptional control of terminal nephron differentiation

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