Clarifying the biological significance of the <scp>CHK</scp>2 K373E somatic mutation discovered in The Cancer Genome Atlas database

Higashiguchi, Masayoshi; Nagatomo, Izumi; Kijima, Takashi; Morimura, Osamu; Miyake, Kotaro; Minami, Toshiyuki; Koyama, Shohei; Hirata, Haruhiko; Iwahori, Kota; Takimoto, Takayuki; Takeda, Yoshito; Kida, Hiroshi; Kumanogoh, Atsushi

doi:10.1002/1873-3468.12449

Cited by 8 publications

(5 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, a negative correlation between CHK2 and cell and tissue turnover has been reported [42]. In addition, CHK2 germline mutations and rare somatic mutations have been detected with high incidence in a number of familial cancers in humans, including prostate, breast, ovarian, thyroid, kidney, colorectal and bladder cancers, and leukemias [43,44], suggesting that CHK2 may be a good target in cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

SIRT1 modulates cell cycle progression by regulating CHK2 acetylation−phosphorylation

et al. 2019

View full text Add to dashboard Cite

Both the stress-response protein, SIRT1, and the cell cycle checkpoint kinase, CHK2, play critical roles in aging and cancer via the modulation of cellular homeostasis and the maintenance of genomic integrity. However, the underlying mechanism linking the two pathways remains elusive. Here, we show that SIRT1 functions as a modifier of CHK2 in cell cycle control. Specifically, SIRT1 interacts with CHK2 and deacetylates it at lysine 520 residue, which suppresses CHK2 phosphorylation, dimerization, and thus activation. SIRT1 depletion induces CHK2 hyperactivation-mediated cell cycle arrest and subsequent cell death. In vivo, genetic deletion of Chk2 rescues the neonatal lethality of Sirt1 −/− mice, consistent with the role of SIRT1 in preventing CHK2 hyperactivation. Together, these results suggest that CHK2 mediates the function of SIRT1 in cell cycle progression, and may provide new insights into modulating cellular homeostasis and maintaining genomic integrity in the prevention of aging and cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

SIRT1 modulates cell cycle progression by regulating CHK2 acetylation−phosphorylation

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Outside of the IR literature, multiple studies confirm that mutations can increase proliferation, hyperplasia, and tumors (Podsypanina et al 2008). Mutations in cell cycle checkpoint, growth factor signaling, and other genes enable mammary epithelial and other cells to proliferate in vitro (Gustin et al 2009;Higashiguchi et al 2016;Kouros-Mehr et al 2006;Shahi et al 2017;Tao et al 2011), promote mammary hyperplasia in vivo (Francis et al 2009), and contribute to tumors when combined with the other mutations in the same pathway (Francis et al 2011). Restoring function in mutated genes regresses tumors in animals (Martins et al 2006;Podsypanina et al 2008).…”

Section: Essentiality Of Dna Damage Gi and Mutationmentioning

confidence: 99%

Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast

Helm

Rudel

2020

Arch Toxicol

View full text Add to dashboard Cite

Knowledge about established breast carcinogens can support improved and modernized toxicological testing methods by identifying key mechanistic events. Ionizing radiation (IR) increases the risk of breast cancer, especially for women and for exposure at younger ages, and evidence overall supports a linear dose-response relationship. We used the Adverse Outcome Pathway (AOP) framework to outline and evaluate the evidence linking ionizing radiation with breast cancer from molecular initiating events to the adverse outcome through intermediate key events, creating a qualitative AOP. We identified key events based on review articles, searched PubMed for recent literature on key events and IR, and identified additional papers using references. We manually curated publications and evaluated data quality. Ionizing radiation directly and indirectly causes DNA damage and increases production of reactive oxygen and nitrogen species (RONS). RONS lead to DNA damage and epigenetic changes leading to mutations and genomic instability (GI). Proliferation amplifies the effects of DNA damage and mutations leading to the AO of breast cancer. Separately, RONS and DNA damage also increase inflammation. Inflammation contributes to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS and DNA damage, and separately increases proliferation and breast cancer through pro-carcinogenic effects on cells and tissue. For example, gene expression changes alter inflammatory mediators, resulting in improved survival and growth of cancer cells and a more hospitable tissue environment. All of these events overlap at multiple points with events characteristic of "background" induction of breast carcinogenesis, including hormone-responsive proliferation, oxidative activity, and DNA damage. These overlaps make the breast particularly susceptible to ionizing radiation and reinforce that these biological activities are important characteristics of carcinogens. Agents that increase these biological processes should be considered potential breast carcinogens, and predictive methods are needed to identify chemicals that increase these processes. Techniques are available to measure RONS, DNA damage and mutation, cell proliferation, and some inflammatory proteins or processes. Improved assays are needed to measure GI and chronic inflammation, as well as the interaction with hormonally driven development and proliferation. Several methods measure diverse epigenetic changes, but it is not clear which changes are relevant to breast cancer. In addition, most toxicological assays are not conducted in mammary tissue, and so it is a priority to evaluate if results from other tissues are generalizable to breast, or to conduct assays in breast tissue. Developing and applying these assays to identify exposures of concern will facilitate efforts to reduce subsequent breast cancer risk.Biological systems studied This review article summarizes and synthesizes data from cell-culture, experimental animals, and human epidem...

show abstract

“…CHEK2 is a cell-cycle checkpoint gene and has been shown to phosphorylate both BRCA1 and P53 [ 93 ]. Cancer-associated mutations of CHEK2 are generally inactivating, which impairs its ability to suppress cell proliferation [ 94 ]. Hereditary mutations in CHEK2 have also been shown to predispose patients to multiple cancer types [ 95 ].…”

Section: Resultsmentioning

confidence: 99%

A Genome-Wide Profiling of Glioma Patients with an IDH1 Mutation Using the Catalogue of Somatic Mutations in Cancer Database

Pappula

Rasheed

Mirzaei

et al. 2021

Cancers

View full text Add to dashboard Cite

Gliomas are differentiated into two major disease subtypes, astrocytoma or oligodendroglioma, which are then characterized as either IDH (isocitrate dehydrogenase)-wild type or IDH-mutant due to the dramatic differences in prognosis and overall survival. Here, we investigated the genetic background of IDH1-mutant gliomas using the Catalogue of Somatic Mutations in Cancer (COSMIC) database. In astrocytoma patients, we found that IDH1 is often co-mutated with TP53, ATRX, AMBRA1, PREX1, and NOTCH1, but not CHEK2, EGFR, PTEN, or the zinc finger transcription factor ZNF429. The majority of the mutations observed in these genes were further confirmed to be either drivers or pathogenic by the Cancer-Related Analysis of Variants Toolkit (CRAVAT). Gene expression analysis showed down-regulation of DRG2 and MSN expression, both of which promote cell proliferation and invasion. There was also significant over-expression of genes such as NDRG3 and KCNB1 in IDH1-mutant astrocytoma patients. We conclude that IDH1-mutant glioma is characterized by significant genetic changes that could contribute to a better prognosis in glioma patients.

show abstract

Clarifying the biological significance of the CHK2 K373E somatic mutation discovered in The Cancer Genome Atlas database

Cited by 8 publications

References 33 publications

SIRT1 modulates cell cycle progression by regulating CHK2 acetylation−phosphorylation

SIRT1 modulates cell cycle progression by regulating CHK2 acetylation−phosphorylation

Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast

A Genome-Wide Profiling of Glioma Patients with an IDH1 Mutation Using the Catalogue of Somatic Mutations in Cancer Database

Contact Info

Product

Resources

About