p53 gain‐of‐function mutations increase Cdc7‐dependent replication initiation

Datta, Asoke G.; Ghatak, Dishari; Das, Sumit; Banerjee, Taraswi; Paul, Anindita; Butti, Ramesh; Gorain, Mahadeo; Ghuwalewala, Sangeeta; Roychowdhury, Anirban; Alam, Sk Kayum; Das, Pritha; Chatterjee, Raghunath; Dasgupta, Moumita; Panda, Chinmay Kumar; Kundu, Gopal C.; Roychoudhury, Susanta

doi:10.15252/embr.201643347

Cited by 40 publications

(31 citation statements)

References 55 publications

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“…In most of these cases, p53 gene has been reported to contain missense mutations [36][37][38][39]. The mutant p53 proteins no longer have tumor suppressor activity, and obtain several gainof-functions such as invasion [40][41][42][43][44][45][46][47][48], enhanced migration [42,[49][50][51][52], anchorage-independent growth [53][54][55][56][57][58], propagation of cell cycle [59][60][61][62][63][64][65], cell survival and avoidance of cell death [66][67][68][69][70][71][72][73][74][75][76], genomic instability [77][78][79][80][81][82], and angiogenesis…”

Section: Overlapping Molecules Between Cancer and Neurodegenerative Dmentioning

confidence: 99%

Molecular crosstalk between cancer and neurodegenerative diseases

Seo

Park

2019

Cell. Mol. Life Sci.

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The progression of cancers and neurodegenerative disorders is largely defined by a set of molecular determinants that are either complementarily deregulated, or share remarkably overlapping functional pathways. A large number of such molecules have been demonstrated to be involved in the progression of both diseases. In this review, we particularly discuss our current knowledge on p53, cyclin D, cyclin E, cyclin F, Pin1 and protein phosphatase 2A, and their implications in the shared or distinct pathways that lead to cancers or neurodegenerative diseases. In addition, we focus on the interdependent regulation of brain cancers and neurodegeneration, mediated by intercellular communication between tumor and neuronal cells in the brain through the extracellular microenvironment. Finally, we shed light on the therapeutic perspectives for the treatment of both cancer and neurodegenerative disorders. Keywords Age-related diseases • Cell death • Cell survival • Redox system • Glioma • Neurotoxicity Abbreviations Aβ Amyloid-β AD Alzheimer's disease ALS Amyotrophic lateral sclerosis AMPA α-Amino-3-hydroxy-5-methyl-4isoxazolepropionate APC/C Anaphase promoting complex/ cyclosome APP Amyloid precursor protein ATRA All-trans retinoic acid APL Acute promyelocytic leukemia Bax Bcl-2 associated X BH3 Bcl-2 homology 3 Bim Bcl-2-interacting mediator of cell death BimEL Bim-extra long CDK Cyclin-dependent kinase Cellular and Molecular Life Sciences

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Section: Overlapping Molecules Between Cancer and Neurodegenerative Dmentioning

confidence: 99%

Molecular crosstalk between cancer and neurodegenerative diseases

Seo

Park

2019

Cell. Mol. Life Sci.

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“…While del17p, which includes the TP53 gene, is a known high-risk marker in MM, variability in cytogenetic assay cutoff has resulted in a heterogenous population of patients with this abnormality being designated as high-risk. The Myeloma Genome Project (MGP) has identified high-risk patients using molecular methods to circumvent challenges associated with P53 [22,[30][31][32][33][34][35][36][37]. In contrast, other studies suggest that missense mutations in TP53 are loss of function (LOF) and act through a dominant-negative mechanism affecting oligomerization [38][39][40][41][42].…”

Section: Introductionmentioning

confidence: 99%

Prognosis, Biology, and Targeting of TP53 Dysregulation in Multiple Myeloma

Flynt¹,

Bisht²,

Sridharan³

et al. 2020

Cells

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Multiple myeloma (MM) is the second most common hematological cancer and is characterized by genetic features including translocations, chromosomal copy number aberrations, and mutations in key oncogene and tumor suppressor genes. Dysregulation of the tumor suppressor TP53 is important in the pathogenesis of many cancers, including MM. In newly-diagnosed MM patients, TP53 dysregulation occurs in three subsets: monoallelic deletion as part of deletion of chromosome 17p (del17p) (~8%), monoallelic mutations (~6%), and biallelic inactivation (~4%). Del17p is an established high-risk feature in MM and is included in current disease staging criteria. Biallelic inactivation and mutation have also been reported in MM patients but are not yet included in disease staging criteria for high-risk disease. Emerging clinical and genomics data suggest that the biology of high-risk disease is complex, and so far, traditional drug development efforts to target dysregulated TP53 have not been successful. Here we review the TP53 dysregulation literature in cancer and in MM, including the three segments of TP53 dysregulation observed in MM patients. We propose a reverse translational approach to identify novel targets and disease drivers from TP53 dysregulated patients to address the unmet medical need in this setting.

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“…Aberrations in DNA replication are a major cause to tumorigenesis and genome instability, a hallmark of cancer cells [ 5 ]. Indeed, overexpression of Cdc7 is associated with tumor advanced clinical stage, cell cycle deregulation, and genomic instability in ovarian [ 6 ], breast cancer [ 7 ], lung adenocarcinoma [ 8 ], and oral cancer [ 9 ]. Additionally, Dbf4 overexpression is associated with lower relapse-free survival in cutaneous melanoma [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Cdc7 Kinase Inhibitors as Anti-Cancer Agents that Target the Interaction with Dbf4 by the Fragment Complementation and Drug Repositioning Approach

Cheng

Yang

et al. 2018

EBioMedicine

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BackgroundCdc7-Dbf4 is a conserved serine/threonine kinase that plays an important role in initiation of DNA replication and DNA damage tolerance in eukaryotic cells. Cdc7 has been found overexpressed in human cancer cell lines and tumor tissues, and the knockdown of Cdc7 expression causes an p53-independent apoptosis, suggesting that Cdc7 is a target for cancer therapy. Only a handful Cdc7 kinase inhibitors have been reported. All Cdc7 kinase inhibitors, including PHA-767491, were identified and characterized as ATP-competitive inhibitors. Unfortunately, these ATP-competitive Cdc7 inhibitors have no good effect on clinical trial.MethodsHere, we have developed a novel drug-screening platform to interrupt the interaction between Cdc7 and Dbf4 based on Renilla reniformis luciferase (Rluc)-linked protein-fragment complementation assay (Rluc-PCA). Using drug repositioning approach, we found several promising Cdc7 inhibitors for cancer therapy from a FDA-approved drug library.FindingsOur data showed that dequalinium chloride and clofoctol we screened inhibit S phase progression, accumulation in G2/M phase, and Cdc7 kinase activity. In addition, in vivo mice animal study suggests that dequalinium chloride has a promising anti-tumor activity in oral cancer. Interestingly, we also found that dequalinium chloride and clofoctol sensitize the effect of platinum compounds and radiation due to synergistic effect. In conclusion, we identified non-ATP-competitive Cdc7 kinase inhibitors that not only blocks DNA synthesis at the beginning but also sensitizes cancer cells to DNA damage agents.InterpretationThe inhibitors will be a promising anti-cancer agent and enhance the therapeutic effect of chemotherapy and radiation for current cancer therapy.FundThis work was supported by grants from the Ministry of Science and Technology, Ministry of Health and Welfare, and National Health Research Institutes, Taiwan.

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p53 gain‐of‐function mutations increase Cdc7‐dependent replication initiation

Cited by 40 publications

References 55 publications

Molecular crosstalk between cancer and neurodegenerative diseases

Molecular crosstalk between cancer and neurodegenerative diseases

Prognosis, Biology, and Targeting of TP53 Dysregulation in Multiple Myeloma

Identification of Novel Cdc7 Kinase Inhibitors as Anti-Cancer Agents that Target the Interaction with Dbf4 by the Fragment Complementation and Drug Repositioning Approach

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