Abstract:
:Cancer-associated p53 missense mutants confer gain of function (GOF) and promote tumorigenesis by regulating crucial signaling pathways. However, the role of GOF mutant p53 in regulating DNA replication, a commonly altered pathway in cancer, is less explored. Here, we show that enhanced Cdc7-dependent replication initiation enables mutant p53 to confer oncogenic phenotypes. We demonstrate that mutant p53 cooperates with the oncogenic transcription factor Myb in vivo and transactivates Cdc7 in cancer cells. Moreover, mutant p53 cells exhibit enhanced levels of Dbf4, promoting the activity of Cdc7/Dbf4 complex. Chromatin enrichment of replication initiation factors and subsequent increase in origin firing confirm increased Cdc7-dependent replication initiation in mutant p53 cells. Further, knockdown of CDC7 significantly abrogates mutant p53-driven cancer phenotypes in vitro and in vivo Importantly, high CDC7 expression significantly correlates with p53 mutational status and predicts poor clinical outcome in lung adenocarcinoma patients. Collectively, this study highlights a novel functional interaction between mutant p53 and the DNA replication pathway in cancer cells. We propose that increased Cdc7-dependent replication initiation is a hallmark of p53 gain-of-function mutations.
journal_name
EMBO Repjournal_title
EMBO reportsauthors
Datta A,Ghatak D,Das S,Banerjee T,Paul A,Butti R,Gorain M,Ghuwalewala S,Roychowdhury A,Alam SK,Das P,Chatterjee R,Dasgupta M,Panda CK,Kundu GC,Roychoudhury Sdoi
10.15252/embr.201643347subject
Has Abstractpub_date
2017-11-01 00:00:00pages
2030-2050issue
11eissn
1469-221Xissn
1469-3178pii
embr.201643347journal_volume
18pub_type
杂志文章相关文献
EMBO REPORTS文献大全abstract::Cortical pulling forces on astral microtubules are essential to position the spindle. These forces are generated by cortical dynein, a minus-end directed motor. Previously, another dynein regulator termed Spindly was proposed to regulate dynein-dependent spindle positioning. However, the mechanism of how Spindly regul...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.15252/embr.201541143
更新日期:2016-03-01 00:00:00
abstract::Impairment of PINK1/parkin-mediated mitophagy is currently proposed to be the molecular basis of mitochondrial abnormality in Parkinson's disease (PD). We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. Drp1S616 phosphorylation is significantly reduced in cells and mouse tissues deficient for PINK1, ...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.15252/embr.201948686
更新日期:2020-08-05 00:00:00
abstract::Reading the academic literature is an essential part of a scientist's job. David Smith argues that reading fiction can be even more important for creativity and productivity than papers and reviews. ...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.15252/embr.202052206
更新日期:2021-01-04 00:00:00
abstract::Centromeric constitutive heterochromatin is marked by DNA methylation and dimethylated histone H3 Lys 9 (H3K9me2) in Arabidopsis. RNA-directed DNA methylation (RdDM) is a process that uses 24-nucleotide (nt) small interfering RNAs (siRNAs) to induce de novo methylation to its homologous DNA sequences. Despite the pres...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.1038/embor.2009.152
更新日期:2009-09-01 00:00:00
abstract::The Ark/Prk serine/threonine kinases initiate phosphorylation cycles that control the endocytic machinery in mammalian cells and in yeast, and the actin cytoskeleton in yeast. The members of this protein family are unified by homologies in their kinase domain, but are generally diverse in their other domains. The evol...
journal_title:EMBO reports
pub_type: 杂志文章,评审
doi:10.1038/sj.embor.embor776
更新日期:2003-03-01 00:00:00
abstract::Ubiquitylation is an essential post-translational modification that regulates numerous cellular processes, most notably protein degradation. Ubiquitin can itself be phosphorylated at nearly every serine, threonine, and tyrosine residue. However, the effect of this modification on ubiquitin function is largely unknown....
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.15252/embr.201540298
更新日期:2015-09-01 00:00:00
abstract::Recruitment of beta-arrestin (beta-arr) to agonist-stimulated G-protein-coupled receptors (GPCRs) has a crucial role in controlling signalling efficacy and selectivity. When translocated to the receptor, beta-arr is believed to undergo important conformational rearrangement necessary for its downstream actions. To pro...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.1038/sj.embor.7400373
更新日期:2005-04-01 00:00:00
abstract::The active and inactive X chromosomes have distinct epigenetic marks in somatic nuclei, which undergo reprogramming after transplantation into oocytes. We show that, despite the disappearance of Xist RNA coating in 30 min, the epigenetic memory of the inactive X persists with the precocious appearance of histone H3 tr...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.1038/sj.embor.7400461
更新日期:2005-08-01 00:00:00
abstract::Somatic hypermutation of immunoglobulin variable genes, which increases antibody diversity, is initiated by the activation-induced cytosine deaminase (AID) protein. The current DNA-deamination model posits that AID deaminates cytosine to uracil in DNA, and that mutations are generated by DNA polymerases during replica...
journal_title:EMBO reports
pub_type: 杂志文章,评审
doi:10.1038/sj.embor.7400582
更新日期:2005-12-01 00:00:00
abstract::Paxillin is a protein containing four LIM domains, and functions in integrin signaling. We report here that two transcripts are generated from the paxillin gene locus in Drosophila; one encodes a protein homolog of the vertebrate Paxillin (DPxn37), and the other a protein with only three LIM domains, partly encoded by...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.1093/embo-reports/kve178
更新日期:2001-09-01 00:00:00
abstract::The first EMBO Conference on Experimental Approaches to Evolution and Ecology in Yeast was held in Heidelberg, Germany, at the end of September 2010. What might sound like a rather narrow topic actually covered a broad range of interests, approaches, and systems and generated a great deal of excitement among participa...
journal_title:EMBO reports
pub_type:
doi:10.1038/embor.2010.204
更新日期:2011-01-01 00:00:00
abstract::The second edition of the EMBO Spatial meeting took place in May 2011 in Engelberg, Switzerland. Although the work presented at the meeting covered a challengingly broad range of topics, it accomplished the rare goal of promoting interactions between cell biologists, neuroscientists, systems biologists and mathematici...
journal_title:EMBO reports
pub_type:
doi:10.1038/embor.2011.169
更新日期:2011-09-01 00:00:00
abstract::The actin cytoskeleton operates in a multitude of cellular processes including cell shape and migration, mechanoregulation, and membrane or organelle dynamics. However, its filamentous properties and functions inside the mammalian cell nucleus are less well explored. We previously described transient actin assembly at...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.15252/embr.202050758
更新日期:2020-11-05 00:00:00
abstract::Short interfering RNAs (siRNAs) are short (21-23 nt) double-stranded RNAs that direct the sequence-specific degradation of corresponding mRNAs, resulting in suppression of gene activity. siRNAs are powerful tools for gene functional analysis in mammals. Chemically synthesized siRNAs permit transient gene repression bu...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.1038/sj.embor.7400064
更新日期:2004-02-01 00:00:00
abstract::Drosophila ovarian germline stem cells (GSCs) are maintained by the extracellular BMP2/4 orthologue Dpp, which is produced from the surrounding somatic niche. The Dpp signal has a short range; it induces a response in GSCs within the niche, but is rapidly extinguished in their progeny only one cell-diameter away. To e...
journal_title:EMBO reports
pub_type: 杂志文章,评审
doi:10.1038/embor.2011.80
更新日期:2011-06-01 00:00:00
abstract::The Vav family of proteins are guanine nucleotide exchange factors (GEFs) for the Rho family of GTPases, which regulate various cellular functions, including T-cell activation. They contain a catalytic Dbl homology (DH) domain that is invariably followed by a pleckstrin homology (PH) domain, which is often required fo...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.1038/embor.2008.80
更新日期:2008-07-01 00:00:00
abstract::The Polycomb group (PcG) of proteins conveys epigenetic inheritance of repressed transcriptional states. In Drosophila, the Polycomb repressive complex 1 (PRC1) maintains the silent state by inhibiting the transcription machinery and chromatin remodelling at core promoters. Using immunoprecipitation of in vivo formald...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.1038/sj.embor.7400260
更新日期:2004-10-01 00:00:00
abstract::Recent work has brought to light many different mechanisms of translation initiation that function in cells in parallel to canonical cap-dependent initiation. This has important implications for cancer. Canonical cap-dependent translation initiation is inhibited by many stresses such as hypoxia, nutrient limitation, p...
journal_title:EMBO reports
pub_type: 杂志文章,评审
doi:10.15252/embr.201845947
更新日期:2018-10-01 00:00:00
abstract::Streptococcus pneumoniae causes more than one million deaths every year, mostly of young children in developing countries, due to pneumonia, bacteremia and meningitis. The emergence and dissemination of drug-resistant pneumococcal strains, coupled to changing patterns of virulence and the inadequacy of available vacci...
journal_title:EMBO reports
pub_type: 杂志文章,评审
doi:10.1093/embo-reports/kvf152
更新日期:2002-08-01 00:00:00
abstract::Very little is known about the biogenesis and assembly of oligomeric membrane proteins. In this study, the biogenesis of KcsA, a prokaryotic homotetrameric potassium channel, is investigated. Using in vivo pulse-chase experiments, both the monomeric and tetrameric form could be identified. The conversion of monomers i...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.1093/embo-reports/kvd067
更新日期:2000-10-01 00:00:00
abstract::Mitochondria play a central role in stem cell homeostasis. Reversible switching between aerobic and anaerobic metabolism is critical for stem cell quiescence, multipotency, and differentiation, as well as for cell reprogramming. However, the effect of mitochondrial dysfunction on neural stem cell (NSC) function is uns...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.15252/embr.201540982
更新日期:2015-11-01 00:00:00
abstract::The ubiquitin-binding zinc finger (UBZ) domain of human DNA Y-family polymerase (pol) eta is important in the recruitment of the polymerase to the stalled replication machinery in translesion synthesis. Here, we report the solution structure of the pol eta UBZ domain and its interaction with ubiquitin. We show that th...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.1038/sj.embor.7400901
更新日期:2007-03-01 00:00:00
abstract::The hypoxic response in humans is mediated by the hypoxia-inducible transcription factor (HIF), for which prolyl hydroxylases (PHDs) act as oxygen-sensing components. The evolutionary origins of the HIF system have been previously unclear. We demonstrate a functional HIF system in the simplest animal, Trichoplax adhae...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.1038/embor.2010.170
更新日期:2011-01-01 00:00:00
abstract::Plasma membrane PI4P is an important direct regulator of many processes that occur at the plasma membrane and also a biosynthetic precursor of PI(4,5)P2 and its downstream metabolites. The majority of this PI4P pool is synthesized by an evolutionarily conserved complex, which has as its core the PI 4-kinase PI4KIIIα (...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.15252/embr.201439151
更新日期:2015-03-01 00:00:00
abstract::Nuclear components are functionally linked with the dynamic temporal and spatial compartmentalization, sorting and integration of regulatory information to facilitate its selective use. For example, the subnuclear targeting of transcription factors to punctate sites in the interphase nucleus mechanistically couples ch...
journal_title:EMBO reports
pub_type: 杂志文章,评审
doi:10.1038/sj.embor.7400337
更新日期:2005-02-01 00:00:00
abstract::Autophagosome formation is promoted by the PI3 kinase complex and negatively regulated by myotubularin phosphatases, indicating that regulation of local phosphatidylinositol 3-phosphate (PtdIns3P) levels is important for this early phase of autophagy. Here, we show that the Caenorhabditis elegans myotubularin phosphat...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.15252/embr.201438618
更新日期:2014-09-01 00:00:00
abstract::Subcellular organization is yielding to large-scale analysis. Researchers are now applying robust mass-spectrometry-based proteomics methods to obtain an inventory of biochemically isolated organelles that contain hundreds of proteins. High-resolution methods allow accurate protein identification, and novel algorithms...
journal_title:EMBO reports
pub_type: 杂志文章,评审
doi:10.1038/sj.embor.7400780
更新日期:2006-09-01 00:00:00
abstract::WDR11 has been implicated in congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS), human developmental genetic disorders defined by delayed puberty and infertility. However, WDR11's role in development is poorly understood. Here, we report that WDR11 modulates the Hedgehog (Hh) signalling pathway ...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.15252/embr.201744632
更新日期:2018-02-01 00:00:00
abstract::RNA silencing is a complex of mechanisms that regulate gene expression through small RNA molecules. The microRNA (miRNA) pathway is the most common of these in mammals. Genome-encoded miRNAs suppress translation in a sequence-specific manner and facilitate shifts in gene expression during developmental transitions. He...
journal_title:EMBO reports
pub_type: 杂志文章,评审
doi:10.1038/embor.2010.102
更新日期:2010-08-01 00:00:00
abstract::CLIP-170/Restin belongs to a family of conserved microtubule (MT)-associated proteins, which are important for MT organization and functions. CLIP-170 is a phosphoprotein and phosphorylation is thought to regulate the binding of CLIP-170 to MTs. However, little is known about the kinase(s) involved. In this study, we ...
journal_title:EMBO reports
pub_type: 杂志文章
doi:10.1093/embo-reports/kvf197
更新日期:2002-10-01 00:00:00