MAP4K1 Functions as a Tumor Promotor and Drug Mediator for AML via Modulation of DNA Damage/Repair System and MAPK Pathway

2020 ◽  
Author(s):  
Qing Ling ◽  
Fenglin Li ◽  
Xiang Zhang ◽  
Shihui Mao ◽  
Xiangjie Lin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mapk Pathway ◽  
Dna Damage Repair ◽  
Repair System ◽  
Damage Repair ◽  
Tumor Promotor

scholarly journals MAP4K1 functions as a tumor promotor and drug mediator for AML via modulation of DNA damage/repair system and MAPK pathway

EBioMedicine ◽  
2021 ◽  
Vol 69 ◽  
pp. 103441
Author(s):  
Qing Ling ◽  
Fenglin Li ◽  
Xiang Zhang ◽  
Shihui Mao ◽  
Xiangjie Lin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mapk Pathway ◽  
Dna Damage Repair ◽  
Repair System ◽  
Damage Repair ◽  
Tumor Promotor

scholarly journals Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1289 ◽  
Author(s):  
Xing Bian ◽  
Wenchu Lin
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Repair ◽  
Predictive Biomarkers ◽  
Replication Stress ◽  
Genotoxic Stress ◽  
Repair System ◽  
Damage Repair ◽  
Repair Pathways

Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC.

Deeper Insight in Metastatic Cancer progression;Epithelial-to-Mesenchymal Transition and Genomic Instability: implications on treatment resistance

2021 ◽  
Vol 21 ◽  
Author(s):  
Kenneth Omabe ◽  
Sandra Uduituma ◽  
David Igwe ◽  
Maxwell Omabe
Keyword(s):  
Dna Damage ◽  
Cancer Treatment ◽  
Epithelial To Mesenchymal Transition ◽  
Dna Damage Repair ◽  
Treatment Resistance ◽  
Therapy Resistance ◽  
Cellular Reprogramming ◽  
Repair System ◽  
Mesenchymal Transition ◽  
Damage Repair

: Therapy resistance remains the major obstacle to successful cancer treatment. Epithelial-to- mesenchymal transition [EMT], a cellular reprogramming process involved in embryogenesis and organ development and regulated by a number of transcriptional factors [EMT-TFs] such as ZEB1/2, is recognized for its role in tumor progression and metastasis. Recently, a growing body of evidence has implicated EMT in cancer therapy resistance but the actual mechanism that underlie this finding has remained elusive. For example, whether it is, the EMT states in itself or the EMT-TFs that modulates chemo or radio-resistance in cancer is still contentious. Here, we summarise the molecular mechanisms of EMT program and chemotherapeutic resistance in cancer with specific reference to DNA damage response [DDR]. We provide an insight into the molecular interplay that exist between EMT program and DNA repair machinery in cancer and how this interaction influences therapeutic response. We review conflicting studies linking EMT and drug resistance via the DNA damage repair axis. We draw scientific evidence demonstrating how several molecular signalling, including EMT-TFs work in operational harmony to induce EMT and confer stemness properties on the EMT-susceptible cells. We highlight the role of enhanced DNA damage repair system associated with EMT-derived stem cell-like states in promoting therapy resistance and suggest a multi-targeting modality in combating cancer treatment resistance.

scholarly journals Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4200
Author(s):  
Christina Bothou ◽  
Ashish Sharma ◽  
Adrian Oo ◽  
Baek Kim ◽  
Pal Perge ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ribonucleotide Reductase ◽  
Ataxia Telangiectasia ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Dna Damage Repair ◽  
Repair System ◽  
Clinical Patient ◽  
Damage Repair ◽  
Adrenocortical Carcinomas

Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, CHK1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC.

DNA Damage-Repair System and Apoptosis-Related Pathways in Mouse Model of Spinal Cord Ischemia-Reperfusion Injury

2004 ◽  
Vol 10 (S02) ◽  
pp. 1414-1415
Author(s):  
Lei Chen ◽  
Daqing Gao ◽  
Zhaoli Sun ◽  
S H Mcklaren ◽  
Glen Roseborough ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dna Damage ◽  
Mouse Model ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Dna Damage Repair ◽  
Repair System ◽  
Damage Repair

Extended abstract of a paper presented at Microscopy and Microanalysis 2004 in Savannah, Georgia, USA, August 1–5, 2004.

Abstract 125: Proteome Analysis of a Regulatory Pathway of Pathologic Vascular Injury as Mediated by KLF5 and its Transcriptional Complexes

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kenichi Aizawa ◽  
Toru Suzuki ◽  
Takayoshi Mastumura ◽  
Nanae Kada ◽  
Daigo Sawaki ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Proteome Analysis ◽  
Strand Break ◽  
Double Strand Break ◽  
Chain Gene ◽  
Repair System ◽  
Peptide Mass ◽  
Damage Repair ◽  
A Chain

Background: Transcription factor Krüppel-like factor 5 (KLF5) is a key element linking external stress and cardiovascular remodeling by up-regulating platelet derived growth factor (PDGF)-A chain gene activity. However, the underlying mechanisms remain to be elucidated. The unambiguous and comprehensive identification of interacting proteins is crucial for understanding these mechanisms. In the present study, we identified interacting factors of KLF5 by proteomic analysis and characterized their regulation in the vascular pathogenic response. Methods&Results: Double-stranded oligonucleotide containing the binding sequence for KLF5 in the PDGF-A promoter was synthesized and attached to metal beads, to which cell nuclear extract was applied. SDS-PAGE visualized specific bands to the sequence, which were subjected to in-gel digestion and peptide mass fingerprinting by MALDI-TOF/MS spectrometry. Factors that are known to be important in the DNA damage/repair pathway were successively identified. We therefore examined the involvement of the complex in vascular pathologies. Double-strand break as determined by immunohistochemistry using γ-H2AX antibody, a marker of activation of the double-stranded DNA damage/repair response, was observed in pathogenically stimulated vascular endothelial cells (HUVEC) and neointimal tissues in rat carotid artery balloon injury model. Further, KLF5 was shown to mediate the response on γ-H2AX as shown by co-immunoprecipitation and confocal microscopy. Discussion: We show a hitherto unknown regulatory mechanism by DNA double-strand break/repair system involving KLF5 in the vascular pathogenic response. Our findings might provide a clue to understanding the initiation of pathological cell proliferation observed in atherosclerosis or restenosis after coronary intervention. This new pathway might also be a tempting target for therapeutic intervention aimed at modulating the activity of KLF5 upon PDGF-A chain and its associated pathologies in the cardiovascular system.

scholarly journals DNA Damage Repair and DNA Methylation in the Kidney

2019 ◽  
Vol 50 (2) ◽  
pp. 81-91 ◽  
Author(s):  
Kaori Hayashi ◽  
Akihito Hishikawa ◽  
Hiroshi Itoh
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Dna Repair ◽  
Methylation Status ◽  
Dna Damage Repair ◽  
Strand Break ◽  
Repair System ◽  
Damage Repair ◽  
Dna Double Strand Break ◽  
Cell Type Specific

The DNA repair system is essential for the maintenance of genome integrity and is mainly investigated in the areas of aging and cancer. The DNA repair system is strikingly cell-type specific, depending on the expression of DNA repair factors; therefore, different DNA repair systems may exist in each type of kidney cell. Importance of DNA repair in the kidney is suggested by renal phenotypes caused by both genetic mutations in the DNA repair pathway and increased stimuli of DNA damage. Recently, we reported the importance of DNA double-strand break repair in glomerular podocytes and its involvement in the alteration of DNA methylation status, which regulates podocyte phenotypes. In this review, we summarize the roles of the DNA repair system in the kidneys and possible associations with altered kidney DNA methylation, which have been infrequently reported together. Investigations of DNA damage repair and epigenetic changes in the kidneys may achieve a profound understanding of kidney aging and diseases.

scholarly journals Genomic Characterization of Prostatic Ductal Adenocarcinoma Identifies a High Prevalence of DNA Repair Gene Mutations

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Michael T. Schweizer ◽  
Emmanuel S. Antonarakis ◽  
Tarek A. Bismar ◽  
Liana B. Guedes ◽  
Heather H. Cheng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Next Generation Sequencing ◽  
Mapk Pathway ◽  
Dna Damage Repair ◽  
Case Series ◽  
Next Generation ◽  
Repair Gene ◽  
Damage Repair ◽  
Dna Repair Gene ◽  
Generation Sequencing

PURPOSE Ductal prostate cancer (dPC) is a rare variant of prostatic adenocarcinoma associated with poor outcomes. Although its histopathologic features are well characterized, the underlying molecular hallmarks of this aggressive subtype are not well described. We sought to provide a comprehensive overview of the spectrum of mutations associated with dPC. METHODS Three case series across multiple institutions were assembled. All patients had a diagnosis of dPC, and histopathologic classification was confirmed by an expert genitourinary pathologist. Case series 1 included men who were prospectively enrolled in a tumor sequencing study at the University of Washington (n = 22). Case series 2 and 3 included archival samples from men treated at Johns Hopkins Hospital (n = 21) and University of Calgary (n = 8), respectively. Tumor tissue was sequenced on a targeted next-generation sequencing assay, UW-OncoPlex, according to previously published methods. The frequency of pathogenic/likely pathogenic mutations are reported. RESULTS Overall, 25 patients (49%) had at least one DNA damage repair gene alteration, including seven (14%) with a mismatch repair gene mutation and 16 (31%) with a homologous repair mutation. Germline autosomal dominant mutations were confirmed or suspected in 10 patients (20%). Activating mutations in the PI3K pathway (n = 19; 37%), WNT pathway (n = 16; 31%), and MAPK pathway (n = 8; 16%) were common. CONCLUSION This study strongly suggests that dPCs are enriched for actionable mutations, with approximately 50% of patients demonstrating DNA damage repair pathway alteration(s). Patients with dPC should be offered next-generation sequencing to guide standard-of-care treatment (eg, immune checkpoint inhibitors) or triaged toward an appropriate clinical trial (eg, poly [ADP-ribose] polymerase inhibitors).

Sign in / Sign up

Export Citation Format

Share Document