scholarly journals NEK10 tyrosine phosphorylates p53 and controls its transcriptional activity

2019 ◽  
Author(s):  
Nasir Haider ◽  
Previn Dutt ◽  
Bert van de Kooij ◽  
Michael Yaffe ◽  
Vuk Stambolic
Keyword(s):  
Transcriptional Activity ◽  
Cellular Proliferation ◽  
Radiation Treatment ◽  
Transcriptional Response ◽  
Genotoxic Stress ◽  
Breast Cancer Patients ◽  
Dna Damaging Agents ◽  
Damage Response ◽  
Transcriptional Output ◽  
Tumour Suppressor P53

ABSTRACTIn response to genotoxic stress, multiple kinase signalling cascades are activated, many of them directed towards the tumour suppressor p53 which coordinates the DNA damage response (DDR). Defects in DDR pathways lead to an accumulation of mutations that can promote tumorigenesis. Emerging evidence implicates multiple members of the NimA-related kinase (NEK) family (NEK1, NEK10 and NEK11) in the DDR. Here, we describe a function for NEK10 in the regulation of p53 transcriptional activity through tyrosine phosphorylation. NEK10 loss increases cellular proliferation through modulation of the p53-dependent transcriptional output, by directly phosphorylating p53 on Y327, revealing NEK10’s unexpected substrate specificity. A p53 mutant at this site (Y327F) acts as a hypomorph, causing an attenuated p53-mediated transcriptional response. Consistently, NEK10-deficient cells display heightened sensitivity to DNA damaging agents and low NEK10 expression is an independent predictor of a favorable response to radiation treatment in WT TP53 breast cancer patients.

scholarly journals The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells

2014 ◽  
Vol 25 (19) ◽  
pp. 3081-3093 ◽  
Author(s):  
Tetsuya Gotoh ◽  
Marian Vila-Caballer ◽  
Carlo S. Santos ◽  
Jingjing Liu ◽  
Jianhua Yang ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Transcriptional Response ◽  
Genotoxic Stress ◽  
Negative Regulator ◽  
Trimeric Complex ◽  
Physiological Processes ◽  
Period 2 ◽  
Damage Response ◽  
Stress Signals ◽  
Clock Mechanism

Human Period 2 (hPer2) is a transcriptional regulator at the core of the circadian clock mechanism that is responsible for generating the negative feedback loop that sustains the clock. Its relevance to human disease is underlined by alterations in its function that affect numerous biochemical and physiological processes. When absent, it results in the development of various cancers and an increase in the cell's susceptibility to genotoxic stress. Thus we sought to define a yet-uncharacterized checkpoint node in which circadian components integrate environmental stress signals to the DNA-damage response. We found that hPer2 binds the C-terminal half of human p53 (hp53) and forms a stable trimeric complex with hp53’s negative regulator, Mdm2. We determined that hPer2 binding to hp53 prevents Mdm2 from being ubiquitinated and targeting hp53 by the proteasome. Down-regulation of hPer2 expression directly affects hp53 levels, whereas its overexpression influences both hp53 protein stability and transcription of targeted genes. Overall our findings place hPer2 directly at the heart of the hp53-mediated response by ensuring that basal levels of hp53 are available to precondition the cell when a rapid, hp53-mediated, transcriptional response is needed.

scholarly journals Metabolic perturbation of epigenome by inhibiting S-adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831769911 ◽  
Author(s):  
Guozhen Wu ◽  
Ning Wang ◽  
Ying Luo ◽  
Yanyan Zhang ◽  
Peng Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Cellular Senescence ◽  
Genotoxic Stress ◽  
Hepatoma Cells ◽  
Adenosylhomocysteine Hydrolase ◽  
Dna Damaging Agents ◽  
Metabolic Perturbation ◽  
Damage Response

Cellular senescence is a key physiological barrier against tumor and represents an option for therapeutic intervention. One pivotal intracellular stimulus causing senescence is DNA damage response, while the senescence-associated heterochromatin in cancer limits the strength of the DNA damage response to endogenous genotoxic stress or DNA-damaging agents. Therefore, targeting the maintenance of compacted chromatin in cancer cells represents an optional intervention to improve the therapeutic efficacy in cancer treatment. Given a crosstalk between methionine cycle and histone methylation, we hypothesize that pharmacologically disrupting methylation potential, defined as the ratio of cellular S-adenosylmethionine to S-adenosylhomocysteine, could affect the chromatin structures in cancer cells and thus enhance their sensitivity to DNA damage response signaling. Our results showed that 3-deazaneplanocin A, a chemical inhibitor of S-adenosylhomocysteine hydrolase, elicited a typical cellular senescence in hepatoma cells. Therapy-induced senescence by 3-deazaneplanocin A was mediated through p53–p21 pathway and triggered by enhanced ataxia-telangiectasia mutated activation related to chromatin changes. In conclusion, our study demonstrated that metabolic perturbation of chromatin status in oncogene-activated cancers could be an optional intervention to sensitize DNA damage response signaling.

The JNK Pathway Is a Significant Determinant of Sensitivity to DNA Damaging Agents in Pre-B ALL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3786-3786
Author(s):  
Philip O. Saunders ◽  
Kenneth F Bradstock ◽  
Linda J. Bendall
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Dna Damage Response ◽  
Genotoxic Stress ◽  
Jnk Pathway ◽  
Dna Damaging Agents ◽  
Pathway Activation ◽  
Damage Response ◽  
Jnk Activation

Abstract Abstract 3786 Poster Board III-722 The JNK pathway is reported to facilitate AP1 binding and promote apoptosis depending on cell type and environmental conditions. We have previously reported RAD001 (16μM) induces JNK pathway activation in pre-B ALL cells. We sought to evaluate the impact of changes in JNK pathway activation on pre-B ALL viability in vitro. Using JNK inhibitor SP600125 titrated to inhibit c-Jun activation, we determined that cell death in pre-B ALL cells treated with RAD001 (16μM) alone was not JNK dependent. In contrast, combining RAD001 (16μM) with DNA damaging agents significantly enhanced JNK dependent death. This difference indicates that additional factors, including genotoxic stress, are required for JNK activation to induce pre-B ALL cell death. The JNK pathway is reported to suppress transcriptional activation of key mediators of the DNA damage response. We observed that JNK activation in cells treated with RAD001 (16μM) and DNA damaging agents was associated with suppression of p53 and p21 relative to DNA damage alone. This result was supported by the observation of enhanced p53 and p21 expression in pre-B ALL cells treated with DNA damaging agents in the presence of the JNK inhibitor SP600125. Analysis of DNA content and proliferation antigen expression in pre-B ALL cells treated with RAD001 (16μM) and DNA damaging agents revealed JNK activation was associated with a significant increase in the proportion of cells in S phase, relative to DNA damage alone, which caused a G1 and G2 cell cycle arrest. Further evidence that the JNK pathway impacts on the DNA damage response was provided by the observation that pre-B ALL cells treated with DNA damaging agents and JNK inhibitor SP600125 demonstrated reduced PCNA expression at G1 and G2 and reduced expression of mitotic antigen phospho-Histone–H3. This is consistent with enhanced regulation at G1-S and G2-M checkpoints. The results indicate changes in JNK pathway activation impact on the cell cycle response to DNA damage. In conclusion we have identified that the JNK pathway has a significant impact on the sensitivity of pre-B ALL cells to DNA damaging agents. JNK activation in the presence of genotoxic stress significantly enhanced pre-B ALL cell death, associated with suppression of key mediators of the DNA damage response, p53 and p21. We found that changes in JNK activation altered the cell cycle response to DNA damage. Further study is required to determine if changes in cell cycle regulation in the presence of DNA damage is causal to JNK dependent cell death. Additional studies to identify intracellular signal pathways which facilitate JNK dependent cell death are warranted. Our observations suggest combining agents which induce JNK activation with conventional chemotherapy or selected novel agents has the potential to enhance clinical responses in pre-B ALL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tumor hypoxia induces nuclear paraspeckle formation through HIF-2α dependent transcriptional activation of NEAT1 leading to cancer cell survival

Oncogene ◽  
2014 ◽  
Vol 34 (34) ◽  
pp. 4482-4490 ◽  
Author(s):  
H Choudhry ◽  
A Albukhari ◽  
M Morotti ◽  
S Haider ◽  
D Moralli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cell ◽  
Transcriptional Activation ◽  
Cellular Proliferation ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Transcriptional Response ◽  
Clonogenic Survival ◽  
Breast Cancer Cell Lines ◽  
Transcriptional Responses

Abstract Activation of cellular transcriptional responses, mediated by hypoxia-inducible factor (HIF), is common in many types of cancer, and generally confers a poor prognosis. Known to induce many hundreds of protein-coding genes, HIF has also recently been shown to be a key regulator of the non-coding transcriptional response. Here, we show that NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF in many breast cancer cell lines and in solid tumors. Unlike previously described lncRNAs, NEAT1 is regulated principally by HIF-2 rather than by HIF-1. NEAT1 is a nuclear lncRNA that is an essential structural component of paraspeckles and the hypoxic induction of NEAT1 induces paraspeckle formation in a manner that is dependent upon both NEAT1 and on HIF-2. Paraspeckles are multifunction nuclear structures that sequester transcriptionally active proteins as well as RNA transcripts that have been subjected to adenosine-to-inosine (A-to-I) editing. We show that the nuclear retention of one such transcript, F11R (also known as junctional adhesion molecule 1, JAM1), in hypoxia is dependent upon the hypoxic increase in NEAT1, thereby conferring a novel mechanism of HIF-dependent gene regulation. Induction of NEAT1 in hypoxia also leads to accelerated cellular proliferation, improved clonogenic survival and reduced apoptosis, all of which are hallmarks of increased tumorigenesis. Furthermore, in patients with breast cancer, high tumor NEAT1 expression correlates with poor survival. Taken together, these results indicate a new role for HIF transcriptional pathways in the regulation of nuclear structure and that this contributes to the pro-tumorigenic hypoxia-phenotype in breast cancer.

scholarly journals Aberrant CDKN1A transcriptional response associates with abnormal sensitivity to radiation treatment

2008 ◽  
Vol 98 (11) ◽  
pp. 1845-1851 ◽  
Author(s):  
C Badie ◽  
S Dziwura ◽  
C Raffy ◽  
T Tsigani ◽  
G Alsbeih ◽  
...  
Keyword(s):  
Radiation Treatment ◽  
Transcriptional Response

scholarly journals The transcriptional response ofArabidopsisto genotoxic stress - a high-density colony array study (HDCA)

2003 ◽  
Vol 35 (6) ◽  
pp. 771-786 ◽  
Author(s):  
I-Peng Chen ◽  
Urs Haehnel ◽  
Lothar Altschmied ◽  
Ingo Schubert ◽  
Holger Puchta
Keyword(s):  
Transcriptional Response ◽  
Genotoxic Stress ◽  
High Density

Targeting DNA damage response pathways to modulate pancreatic ductal adenocarcinoma sensitivity to DNA damaging agents

Pancreatology ◽  
2016 ◽  
Vol 16 (3) ◽  
pp. S8
Author(s):  
Elaina N. Maginn ◽  
Hani Gabra ◽  
Euan A. Stronach ◽  
Harpreet S. Wasan
Keyword(s):  
Dna Damage ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Dna Damage Response ◽  
Ductal Adenocarcinoma ◽  
Dna Damaging Agents ◽  
Damage Response

scholarly journals AC016745.3 Regulates the Transcription of AR Target Genes by Antagonizing NONO

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1208
Author(s):  
Yali Lu ◽  
Xuechao Wan ◽  
Wenhua Huang ◽  
Lu Zhang ◽  
Jun Luo ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Mechanisms Of Action ◽  
Adenocarcinoma Cell Line ◽  
Specific Mechanism ◽  
Rna Immunoprecipitation ◽  
Non Coding Rnas ◽  
And Migration ◽  
Proliferation And Migration

The androgen receptor (AR) and its related signaling pathways play an important role in the development of prostate cancer (PCa). Long non-coding RNAs (lncRNAs) are involved in the regulation of tumorigenesis and development, but their specific mechanism of action remains unclear. This study examines the function and mechanisms of action of lncRNA AC016745.3 in the development of PCa. It shows that dihydrotestosterone (DHT) results in the AR-dependent suppression of AC016745.3 expression in the LNCaP androgen-sensitive human prostate adenocarcinoma cell line. In addition, overexpression of AC016745.3 inhibits the proliferation and migration of PCa cells, and suppresses the expression of AR target genes. This research also demonstrates that the protein NONO interacts with AR and functions as an AR co-activator, promoting AR transcriptional activity. Furthermore, using RNA immunoprecipitation (RIP)-PCR experiments, the study demonstrates that both NONO and AR can bind AC016745.3. Moreover, cell phenotypic experiments reveal that NONO can promote cellular proliferation and migration, and that AC016745.3 can partially antagonize the pro-oncogenic functions of NONO in PCa cells. In summary, the results indicate that AC016745.3 can bind NONO, suppressing its ability to promote AR-dependent transcriptional activity. Furthermore, DHT-dependent suppression of AC016745.3 expression can enhance NONO’s promotion effect on AR.

scholarly journals DNA damage shifts circadian clock time via Hausp-dependent Cry1 stabilization

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Stephanie J Papp ◽  
Anne-Laure Huber ◽  
Sabine D Jordan ◽  
Anna Kriebs ◽  
Madelena Nguyen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Circadian Clock ◽  
Transcriptional Response ◽  
Genotoxic Stress ◽  
Genomic Integrity ◽  
Clock Time ◽  
Dna Repair Enzymes ◽  
Repair Enzymes ◽  
Specific Protease

The circadian transcriptional repressors cryptochrome 1 (Cry1) and 2 (Cry2) evolved from photolyases, bacterial light-activated DNA repair enzymes. In this study, we report that while they have lost DNA repair activity, Cry1/2 adapted to protect genomic integrity by responding to DNA damage through posttranslational modification and coordinating the downstream transcriptional response. We demonstrate that genotoxic stress stimulates Cry1 phosphorylation and its deubiquitination by Herpes virus associated ubiquitin-specific protease (Hausp, a.k.a Usp7), stabilizing Cry1 and shifting circadian clock time. DNA damage also increases Cry2 interaction with Fbxl3, destabilizing Cry2. Thus, genotoxic stress increases the Cry1/Cry2 ratio, suggesting distinct functions for Cry1 and Cry2 following DNA damage. Indeed, the transcriptional response to genotoxic stress is enhanced in Cry1−/− and blunted in Cry2−/− cells. Furthermore, Cry2−/− cells accumulate damaged DNA. These results suggest that Cry1 and Cry2, which evolved from DNA repair enzymes, protect genomic integrity via coordinated transcriptional regulation.

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