A SNP in the flt-1 promoter integrates the VEGF system into the p53 transcriptional network

Menéndez, Daniel; Krysiak, Oliver; Inga, Alberto; Krysiak, Bianca; Resnick, Michael A.; Schönfelder, Gilbert

doi:10.1073/pnas.0508103103

Cited by 72 publications

(74 citation statements)

References 41 publications

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“…Fitting with this hypothesis, it has been previously reported a transcriptional cooperation between p53 and a ligand-bound estrogen receptor to result in a regulatory cross talk synergistically transactivating VEGFR1/FLT1, whereas p53 alone has relatively no effect. 29,30 In addition, Pax6-downregulated FOXM1 and MCM5 genes were not affected by p53 RNA interference despite it has been reported in other cell systems that p53 could also repress their expression independently of Pax6 signaling. 31,32 Thus, cross talk between Pax6 signaling and p53 activity appears to regulate specific genes in a given environment as the identification of either Pax6 or p53 target genes greatly varies depending on the cell system used.…”

Section: Discussionmentioning

confidence: 80%

Primate-specific RFPL1 gene controls cell-cycle progression through cyclin B1/Cdc2 degradation

et al. 2010

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Ret finger protein-like 1 (RFPL1) is a primate-specific target gene of Pax6, a key transcription factor for pancreas, eye and neocortex development. However, its cellular activity remains elusive. In this article, we report that Pax6-elicited expression of the human (h)RFPL1 gene in HeLa cells can be enhanced by in vivo p53 binding to its promoter and therefore investigated the hypothesis that hRFPL1 regulates cell-cycle progression. Upon expression in these cells, hRFPL1 decreased cell number through a kinase-dependent mechanism as PKC activates and Cdc2 inhibits hRFPL1 activity. hRFPL1 antiproliferative activity led to an increased cell population in G 2 /M phase and specific cyclin B1 and Cdc2 downregulations, which were precluded by a proteasome inhibitor. Specifically, cytoplasm-localized hRFPL1 prevented cyclin B1 and Cdc2 accumulation during interphase. Consequently, cells showed a delayed entry into mitosis and cell-cycle lengthening resulting from a threefold increase in G 2 phase duration. Given previous reports that RFPL1 is expressed during cell differentiation, its impact on cell-cycle lengthening therefore provides novel insights into primate-specific development. The human Ret finger protein-like (hRFPL)1,2,3 genes (OMIM 605968, 605969, 605970) are recently identified targets of Pax6, which is notably a key transcription factor for pancreas, eye and neocortex development. [1][2][3] In this line, high hRFPL1,2,3 expression is found at the onset of neurogenesis in differentiating embryonic stem cells and in the developing neocortex. 4 In addition, the study of RFPL1,2,3 evolutionary history revealed that they are only found in Old World monkeys and great apes and show features believed to be important for human brain evolution. 4 Yet, the cellular activity of RFPL1,2,3 is still unknown. A murine RFPL (mRFPL) protein, encoded by an ancestral gene not belonging to the RFPL1,2,3 gene subfamily, 4 has also been cloned. 5 Previously reported as being expressed only in testis, ovaries and oocytes, 5,6 mRFPL has been shown to interact with the destruction box motif of cyclin B1 -the Cdc2 activating partner for driving germ cells through metaphases I and II 7 -and with proteins of the proteasome, speculating on mRFPL ability to elicit cyclin B1 degradation to control meiosis progression. 6 However, the fact that cyclin B1 and Cdc2 also form a key complex for controlling cell entry into mitosis 8 and our recent observations that the RFPL genes are also expressed in tissues in which cells divide mitotically 4 suggest that the RFPL proteins could regulate other aspects of cell division.We therefore examined RFPL-mediated control of mitotic cell-cycle progression by focusing on hRFPL1. Because no endogenously hRFPL1-expressing cell type suitable for this kind of study has been reported to date, we examined the influence of hRFPL1 gain of function on HeLa cells, a reference cell system for examining cell-cycle regulation. We report that hRFPL1 is an antiproliferative gene that controls G 2 -M phase transition, ...

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Section: Discussionmentioning

confidence: 80%

Primate-specific RFPL1 gene controls cell-cycle progression through cyclin B1/Cdc2 degradation

et al. 2010

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“…Bioinformatic search for the p53 consensus sequence (el-Deiry et al, 1992) revealed two motifs, in the hPar1 promoter residing between À2936 to À2916 and À1704 to À1724, upstream to the PAR1 coding region. Although the first site matches the traditional p53-binding consensus motif with one mismatch, the second site matches only half of the p53-binding consensus motif (Weinberg et al, 2005;Menendez et al, 2006). (H1299 p53/371C).…”

Section: Discussionmentioning

confidence: 99%

p53 controls hPar1 function and expression

Salah

Haupt²,

Maoz

et al. 2008

Oncogene

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Human protease-activated receptor 1 (hPar1) is a bona fide receptor of the hemostatic protease thrombin, and has a central function in tumor progression. Inactivation of the tumor suppressor gene p53 is one of the most common genomic alterations occurring in cancer. Here, we address the interrelations between p53 and hPar1 in cancer. We demonstrate an inverse correlation between hPar1 gene expression and wild-type (wt) p53 levels, and a direct correlation with levels of the mutant (mt) p53. Bioinformatic search revealed the presence of at least two p53 motifs in the hPar1 promoter. Indeed, temperaturesensitive (ts) p53 forms reduced hPar1 promoter activity on wt p53 expression. Ectopic introduction of the p53R175H mutant into cells lacking p53 caused a moderate two-fold induction of hPar1 promoter activity. Chromatin immunoprecipitation (ChIP) analyses confirmed a physical association between the p53 protein and hPar1 chromatin fragments. In parallel, PAR1 function is attenuated by p53, as shown by inhibition of pFAK levels and a Matrigel invasion assay. Ectopic reinforcement of hPar1 rescued the inhibition conferred by p53, confirming that p53 directly affects hPar1 expression and function. Altogether, we provide evidence for a direct binding between p53 and hPar1 chromatin, and assign hPar1 as a target of p53.

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“…Historically, slot blot, Southern blot and cloning and sequencing were used. More recently, immunoprecipitated DNA is PCR amplified and viewed on a gel or with quantitative real-time monitoring [81,82]. Additionally, immunoprecipitated DNA can be measured genome-wide by hybridizing to a genomic tiling microarray, procedurally known as ChIP-on-chip or ChIP-chip [83].…”

Section: Chromatin Immunoprecipitation-a Concern Withmentioning

confidence: 99%

Discovery and verification of functional single nucleotide polymorphisms in regulatory genomic regions: Current and developing technologies

Chorley

Wang

Campbell

et al. 2008

Mutation Research/Reviews in Mutation Research

154

121

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The most common form of genetic variation, single nucleotide polymorphisms or SNPs, can affect the way an individual responds to the environment and modify disease risk. Although most of the millions of SNPs have little or no effect on gene regulation and protein activity, there are many circumstances where base changes can have deleterious effects. Non-synonymous SNPs that result in amino acid changes in proteins have been studied because of their obvious impact on protein activity. It is well known that SNPs within regulatory regions of the genome can result in disregulation of gene transcription. However, the impact of SNPs located in putative regulatory regions, or rSNPs, is harder to predict for two primary reasons. First, the mechanistic roles of non-coding genomic sequence remain poorly defined. Second, experimental validation of the functional consequences of rSNPs is often slow and laborious. In this review, we summarize traditional and novel methodologies for candidate rSNPs selection, in particular in silico techniques that aid in candidate rSNP selection. Additionally we will discuss molecular biological techniques that assess the impact of rSNPs on binding of regulatory machinery, as well as functional consequences on transcription. Standard techniques such as EMSA and luciferase reporter constructs are still widely used to assess effects of rSNPs on binding and gene transcription; however, these protocols are often bottlenecks in the discovery process. Therefore, we highlight novel and developing high-throughput protocols that promise to aid in shortening the process of rSNP validation. Given the large amount of genomic information generated from a multitude of re-sequencing and genome-wide SNP array efforts, future focus should be to develop validation techniques that will allow greater understanding of the impact these polymorphisms have on human health and disease.

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A SNP in the flt-1 promoter integrates the VEGF system into the p53 transcriptional network

Cited by 72 publications

References 41 publications

Primate-specific RFPL1 gene controls cell-cycle progression through cyclin B1/Cdc2 degradation

Primate-specific RFPL1 gene controls cell-cycle progression through cyclin B1/Cdc2 degradation

p53 controls hPar1 function and expression

Discovery and verification of functional single nucleotide polymorphisms in regulatory genomic regions: Current and developing technologies

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