Abstract：
:Loss of p53's tumor-suppressive function, either via TP53 mutation or hyperactive p53 inhibitory proteins, is one of the most frequent events in the development of human cancer. Here, we describe a strategy of pharmacologically inhibiting iASPP, a negative regulator of p53, to restore wild-type p53's tumor-suppressive function. iASPP knockdown in the colon cancer cell line HCT116 efficiently promoted p53's transcriptional activity and induced p53-dependent cell death, suggesting a key role for iASPP in silencing p53 in this cell line. Screening of a preclinical and clinical drug library using isogenic HCT116 cell models revealed that cyclin-dependent kinase 9 (CDK9) inhibitors preferentially inhibit p53+/+, rather than p53-/-, cells. Mechanistically, CDK9 inhibitors downregulated iASPP at the transcriptional level. This downregulation was dose- and time-dependent. CDK9 inhibitors further showed synergistic effects in killing p53+/+ HCT116 cells when combined with the MDM2 inhibitor Nutlin-3. In a large TCGA pan-cancer cohort, iASPP overexpression predicted poor overall survival (OS) in wild-type p53 patients, with worse OS observed when MDM2 was simultaneously overexpressed. Our study identifies CDK9 inhibitors as p53-reactivating agents, and proposes a strategy to treat cancer by efficiently reactivating p53 via the concurrent inhibition of iASPP and MDM2.
journal_name
Cell Signaljournal_title
Cellular signallingauthors
Wu J,Liang Y,Tan Y,Tang Y,Song H,Wang Z,Li Y,Lu Mdoi
10.1016/j.cellsig.2019.109508subject
Has Abstractpub_date
2020-03-01 00:00:00pages
109508eissn
0898-6568issn
1873-3913pii
S0898-6568(19)30304-3journal_volume
67pub_type
杂志文章abstract：:Macrophages are projected as one of the key players responsible for the progression of cancer. Classically activated (M1) macrophages are pro-inflammatory and have a central role in host defense, while alternatively activated (M2) macrophages are associated with immunosuppression. Macrophages residing at the site of n...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2015.03.013
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abstract：:Fas-ligand/CD178 belongs to the TNF family proteins and is the well-characterized inducer of cell death. We showed previously that the interaction of Fas-ligand and caveolin-1 is necessary for Fas-ligand translocation to rafts, and the subsequent induction of Fas-ligand-dependent cell death. Both molecules can undergo...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2020.109590
更新日期：2020-06-01 00:00:00
abstract：:Na(+)/H(+) exchanger-1 (NHE-1) activity is known to play a critical role in the neuronal injury caused by glutamate. However, the underlying mechanism is not clear. This study shows that NHE-1 activation and its phosphorylation during glutamate exposure were attenuated by the inhibition of protein kinase C (PKC)-βI an...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2013.12.011
更新日期：2014-04-01 00:00:00
abstract：:Janus kinase 2 (Jak2) has a pivotal role in erythropoietin (Epo) signaling pathway, including erythrocyte differentiation and Stat5 activation. In the course of screening for critical phosphorylation of tyrosine residues in Jak2, we identified tyrosine 913 (Y(913)) as a novel and functional phosphorylation site, which...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2008.07.008
更新日期：2008-11-01 00:00:00
abstract：:Mice lacking the gene for suppressor of cytokine signaling 1 (SOCS1) show defective homeostasis of T lymphocytes due to accumulation of CD8(+) T cells, resulting at least partly from dysregulated IL-15 signaling. IL-15 alone does not stimulate proliferation of naïve CD8 T cells, but can synergize with IL-21 to induce ...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2006.10.003
更新日期：2007-04-01 00:00:00
abstract：:Lipopolysaccharide (LPS) has been shown to up-regulate the expression of vascular cell adhesion molecule (VCAM)-1 which contributes to the occurrence of airway inflammatory diseases. Genetic analysis reveals the existence of activator protein-1 (AP-1) binding site on VCAM-1 promoter region. However, the role of AP-1 i...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2009.04.006
更新日期：2009-09-01 00:00:00
abstract：:Pancreatic fibrosis, a key feature of chronic pancreatitis and pancreatic cancer, is mediated by activated pancreatic stellate cells (PSC). Connective tissue growth factor (CTGF) has been suggested to play a major role in fibrogenesis by enhancing PSC activation after binding to alpha5beta1 integrin. Here, we have foc...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2008.06.016
更新日期：2008-10-01 00:00:00
abstract：:High levels of VEGF and leptin are strongly linked to worse prognosis of breast cancer. Leptin signalling upregulates VEGF in human and mouse mammary tumor cells (MT), but the specific molecular mechanisms are largely unknown. Pharmacologic and genetic approaches were used to dissect the mechanism of leptin regulation...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2010.05.003
更新日期：2010-09-01 00:00:00
abstract：:Aurora B kinase forms the enzymatic core of the Chromosomal Passenger Complex (CPC) and is a master regulator of mitosis. Understanding the regulation of Aurora B is critical to illuminate its role in mitosis. INCENP, Survivin and Borealin have all been known to promote Aurora B activation. In this study, we have iden...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2012.04.014
更新日期：2012-08-01 00:00:00
abstract：:Activation of the caspase proteases by c-Jun N-terminal kinase 1 (JNK1) has been proposed as a mechanism of apoptotic cell death. Here we report that insulin activates caspase-3 by a pathway requiring phosphatidylinositol 3'-kinase (PI3-kinase). JNK1 assays demonstrated that insulin treatment of myeloma cells induced ...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/s0898-6568(98)00024-2
更新日期：1999-01-01 00:00:00
abstract：:We have shown previously that the angiotensin II (Ang II) receptor AT2 reduces the intracellular levels of cGMP in Xenopus oocytes when activated by ligand binding, and the C-terminal cytoplasmic tail of the AT2 acts as a negative regulator of this function. Here we report the effects of mutations in the 2nd and 3rd i...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2004.08.007
更新日期：2005-03-01 00:00:00
abstract：:It is well established that the IFN-gamma/STAT1 pathway plays an important role in the pancreatic beta-cell apoptosis that is observed in STZ-induced type 1 diabetes; however, the upstream regulatory proteins involved have not been understood. Here, we investigated whether activating transcription factor 3 (ATF3) affe...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2010.06.007
更新日期：2010-11-01 00:00:00
abstract：:In more than 90% of cancers including glioma, telomere elongation reverse transcriptase (hTERT) is overexpressed. In the present study, we sought to explore whether matrix metalloproteinase-9 (MMP-9) shRNA could alter hTERT-mediated proliferation in glioma cells. MMP-9 shRNA induced senescence and apoptosis in glioma ...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2011.08.001
更新日期：2011-12-01 00:00:00
abstract：:The protein kinase C (PKC) family is the most prominent target of tumor-promoting phorbol esters. For the PKCepsilon isozyme, different intracellular localizations and oncogenic potential in several but not all experimental systems have been reported. To obtain information about PKCepsilon-signaling, we investigated t...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2009.01.017
更新日期：2009-05-01 00:00:00
abstract：:The transcription factor Egr-1 is encoded by an immediate early response gene and has been shown to be a key regulator in the induction of apoptosis, mitogenesis and differentiation. It is rapidly induced by different stimuli including the glycoprotein hormone erythropoietin. In this report, we analyse the role of dif...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2008.06.013
更新日期：2008-10-01 00:00:00
abstract：:Quantitative analysis of the proteins which compromise the stimulatory arm of the adenylyl cyclase cascade indicate that the adenylyl cyclase catalytic component is usually the least highly expressed. The effects on both potency of agonist ligands and maximal output resulting from targetted alterations in expression l...
journal_title：Cellular signalling
pub_type： 杂志文章,评审
doi：10.1016/0898-6568(95)02034-9
更新日期：1996-02-01 00:00:00
abstract：:Dengue virus (DENV) infection is a disease that is endemic to many parts of the world, and its increasing prevalence ranks it among the diseases considered to be a significant threat to public health. The clinical manifestations of DENV infection range from mild dengue fever (DF) to more severe dengue hemorrhagic feve...
journal_title：Cellular signalling
pub_type： 杂志文章,评审
doi：10.1016/j.cellsig.2018.05.002
更新日期：2018-08-01 00:00:00
abstract：:Protease-activated receptor 1 (PAR1) is an unusual GPCR that interacts with multiple G protein subfamilies (G(q/11), G(i/o), and G(12/13)) and their linked signaling pathways to regulate a broad range of pathophysiological processes. However, the molecular mechanisms whereby PAR1 interacts with multiple G proteins are...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2012.01.011
更新日期：2012-06-01 00:00:00
abstract：:Sphingolipids and their synthetic enzymes have emerged as critical mediators in numerous diseases including inflammation, aging, and cancer. One enzyme in particular, sphingosine kinase (SK) and its product sphingosine-1-phosphate (S1P), has been extensively implicated in these processes. SK catalyzes the phosphorylat...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2020.109875
更新日期：2021-03-01 00:00:00
abstract：:The effects of ouabain and monensin upon basal and carbachol-stimulated inositol phospholipid breakdown in rat cerebral cortical miniprisms have been investigated. Basal inositol phospholipid breakdown was increased by both compounds at both 6 and 18 mM K+. Enhancement of the carbachol response at 6 mM, but not at 18 ...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/0898-6568(91)90046-w
更新日期：1991-01-01 00:00:00
abstract：:Calmodulin (CaM) antagonists, trifluoperazine (TFP) or calmidazolium (R24571), dose-dependently inhibited cAMP and folic acid (FA) chemotaxis in Dictyostelium. Developing, starved, and refed cells were compared to determine if certain CaM-binding proteins (CaMBPs) and CaM-dependent phosphorylation events could be iden...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/s0898-6568(01)00187-5
更新日期：2001-08-01 00:00:00
abstract：:Transforming growth factor-β (TGF-β) signaling plays a key role in regulating normal cell growth and differentiation, and mutations affecting members of this pathway contribute to cancer development and metastasis. In DNA mismatch repair (MMR)-deficient colorectal cancers that exhibit the microsatellite instability (M...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2016.04.012
更新日期：2016-08-01 00:00:00
abstract：:Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative multifactorial disease characterized, like other diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) or frontotemporal dementia (FTD), by the degeneration of specific neuronal cell populations. Motor neuron loss is distinctive of ALS. However, ...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2010.05.016
更新日期：2010-10-01 00:00:00
abstract：:The p53 tumor suppressor protein is a transcription factor activated by phosphorylation of its N-terminus. MDM2, encoded by a p53-activated gene, acts as a negative-feedback regulator of p53 by promoting p53 degradation. Moreover, MDM2 inhibits p53 by binding to and concealing its N-terminal transcription-activating d...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2015.05.005
更新日期：2015-09-01 00:00:00
abstract：:Caveolin-1 (Cav-1) is a major structural protein of caveolae and plays an important role as a negative regulator of various signaling pathways such as the transforming growth factor-beta (TGF-beta)/smad pathway. In this study, we investigated the role of cav-1 on basal and TGF-beta1-induced expression of type I procol...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2008.02.020
更新日期：2008-07-01 00:00:00
abstract：:MAP Kinase Phosphatase-2 (MKP-2) is a dual specific nuclear phosphatase which is selective for both ERK and JNK, MAP kinases implicated in the regulation of apoptosis in response to genotoxic stress. Here we report the conditional expression of MKP-2 in human embryonic kidney cells 293. We demonstrate that Flag-WT-MKP...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2005.01.003
更新日期：2005-10-01 00:00:00
abstract：:The kidney is one of the fastest-aging organs, and renal senescence has become a major disease affecting human health. Renal cellular senescence is regulated by the joint action of multiple signal transduction pathways. The previous study by our research group found that the Janus kinase 2 (JAK2)/signal transducer and...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2018.10.021
更新日期：2019-01-01 00:00:00
abstract：:In the COS-7 cell signalling network high levels of cAMP produced, for example, by co-stimulation of beta2-adrenergic receptor (beta2-AR) and bradykinin B2 receptor (BKR) may affect epidermal growth factor receptor (EGFR)-mediated activation of extracellular signal-stimulated kinase (ERK). In contrast, co-stimulation ...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2005.08.019
更新日期：2006-07-01 00:00:00
abstract：:Heterotrimeric Galpha12/13 signals induce cellular responses such as serum response element (SRE)-mediated gene transcription via Rho GTPase. Guanine nucleotide exchange factors (GEFs) are strong candidates for linking Galpha signals to Rho. For example, p115 RhoGEF transduces Galpha13 signals to Rho and inhibits Galp...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/s0898-6568(03)00132-3
更新日期：2004-02-01 00:00:00
abstract：:The upstream stimulatory factors 1 (USF1) and 2 (USF2) are transcription factors which bind to E-box motifs of various promoters regulating a variety of different cellular processes. Only little is known about the regulation of USFs. Here, we identified protein kinase CK2 as an enzyme that phosphorylates USF1 but not ...
journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2014.08.028
更新日期：2014-12-01 00:00:00
