Novel Insights into Chk1 Regulation by Phosphorylation

Kasahara, Kousuke; Inagaki, Masaki

doi:10.1247/csf.14017

Cited by 31 publications

(26 citation statements)

References 85 publications

(163 reference statements)

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“…In response to genotoxic stress, Chk1 is phosphorylated and activates DNA damage responses to bring about cell cycle arrest, activate DNA repair pathways, and induce apoptosis when DNA damage is severe (Patil et al, 2013). Chk1 Ser345 phosphorylation is critical for this activation and function in response to DNA damage (Patil et al, 2013; Goto et al, 2015). Higher cellular levels of Chk1 Ser345 phosphorylation were detected in DM331 2C myc cells compared to control cells, suggesting increased activation of Chk1 in melanoma cells with high LAMP-2C expression ( Figure 8A ).…”

Section: Resultsmentioning

confidence: 99%

“…Higher cellular levels of Chk1 Ser345 phosphorylation were detected in DM331 2C myc cells compared to control cells, suggesting increased activation of Chk1 in melanoma cells with high LAMP-2C expression ( Figure 8A ). Although Chk1 is mainly expressed in the nucleus, following activation Chk1 shuttles between the nucleus and cytoplasm (Patil et al, 2013; Goto et al, 2015). Consistent with the increased phosphorylation of Chk1 in cells with ectopic LAMP-2C, slightly more Chk1 protein was detected in the cytoplasm of these cells ( Figure 8B ).…”

Section: Resultsmentioning

confidence: 99%

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Melanoma LAMP-2C Modulates Tumor Growth and Autophagy

Pérez

Sinn

Sandusky

et al. 2018

Front. Cell Dev. Biol.

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Autophagy plays critical but diverse roles in cellular quality control and homeostasis potentially checking tumor development by removing mutated or damaged macromolecules, while conversely fostering tumor survival by supplying essential nutrients during cancer progression. This report documents a novel inhibitory role for a lysosome-associated membrane protein, LAMP-2C in modulating autophagy and melanoma cell growth in vitro and in vivo. Solid tumors such as melanomas encounter a variety of stresses in vivo including inflammatory cytokines produced by infiltrating lymphocytes directed at limiting tumor growth and spread. Here, we report that in response to the anti-tumor, pro-inflammatory cytokine interferon-gamma, melanoma cell expression of LAMP2C mRNA significantly increased. These results prompted an investigation of whether increased melanoma cell expression of LAMP-2C might represent a mechanism to control or limit human melanoma growth and survival. In this study, enhanced expression of human LAMP-2C in melanoma cells perturbed macroautophagy and chaperone-mediated autophagy in several human melanoma lines. In vitro analysis showed increasing LAMP-2C expression in a melanoma cell line, triggered reduced cellular LAMP-2A and LAMP-2B protein expression. Melanoma cells with enhanced LAMP-2C expression displayed increased cell cycle arrest, increased expression of the cell cycle regulators Chk1 and p21, and greater apoptosis and necrosis in several cell lines tested. The increased abundance of Chk1 protein in melanoma cells with increased LAMP-2C expression was not due to higher CHEK1 mRNA levels, but rather an increase in Chk1 protein abundance including Chk1 molecules phosphorylated at Ser345. Human melanoma cell xenografts with increased LAMP-2C expression, displayed reduced growth in immune compromised murine hosts. Melanomas with high LAMP-2C expression showed increased necrosis and reduced cell density upon histological analysis. These results reveal a novel role for LAMP-2C in negatively regulating melanoma growth and survival.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Melanoma LAMP-2C Modulates Tumor Growth and Autophagy

Pérez

Sinn

Sandusky

et al. 2018

Front. Cell Dev. Biol.

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“…CHK1 is an enzyme, essential for preventing mitosis in response to DNA damage, primarily responding to replication fork interference in the S-phase and DNA damage in the G2 phase (13,14). CHK1 kinase regulates the cell cycle progression from S to M phase following disruption of DNA replication or some types of DNA damage and has also been reported to play a role in the S phase in undisturbed cells (15,16).…”

Section: Introductionmentioning

confidence: 99%

Significant expression of CHK1 and p53 in bladder urothelial carcinoma as potential therapeutic targets and prognosis

et al. 2017

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Abstract. Checkpoint kinase 1 (CHK1) and p53 are involved in cell-cycle checkpoint, and cellular response to DNA damage. CHK1 and p53 are overexpressed in bladder urothelial carcinoma (BUC); however, a clear elucidation on their interaction and influence in the progress of BUC is absent. The aim of the present study was to examine the correlation between CHK1 and p53 in BUC, and analyze their value as therapeutic targets and prognostic indicators in BUC. A clinically annotated cohort of 110 patients with BUC was identified retrospectively. EnVision-based immunohistochemistry and western blot analysis of the aforementioned DNA repair proteins were conducted on formalin-fixed-paraffin-emb edded or frozen tissues from the primary tumor. A total of 45 peritumoral tissue cases were assessed similarly as the control group. In the cohort of 110 patients with BUC, a significant overexpression of CHK1 and p53 was observed in primary compared with the peritumoral tissues (P<0.05). CHK1 and p53 demonstrated a positive correlation in BUC, and both were positively associated with the histological grade, clinical pathological staging, lymphatic metastasis and the 5-year survival rate (P<0.05). However, CHK1 and p53 were not associated with sex, age, tumor diameter, single/multiple sites or incipient/recurrence. The overexpression of CHK1 and p53, and their synergistic interaction were putatively correlated with the physiology of BUC that may be deemed as potential therapeutic targets and prognostic indicators.

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“…Atr and Chk1 are also active in unperturbed normal cell cycle progression where the role is to regulate Cdk activity and to prevent late-origin firing [8, 16]. Initiation of replication is determined by Cdk activity, which is regulated negatively by phosphorylation of residue Tyr15 by the Wee1 kinase and positively by its dephosphorylation by Cdc25 phosphatase.…”

Section: Introductionmentioning

confidence: 99%

LAMMER kinase contributes to genome stability in Ustilago maydis

et al. 2015

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Here we report identification of the lkh1 gene encoding a LAMMER kinase homolog (Lkh1) from a screen for DNA repair-deficient mutants in Ustilago maydis. The mutant allele isolated results from a mutation at glutamine codon 488 to a stop codon that would be predicted to lead to truncation of the carboxy-terminal kinase domain of the protein. This mutant (lkh1Q488②) is highly sensitive to ultraviolet light, methyl methanesulfonate, and hydroxyurea. In contrast, a null mutant (lkh1Δ) deleted of the entire lkh1 gene has a less severe phenotype. No epistasis was observed when an lkh1Q488② rad51Δ double mutant was tested for genotoxin sensitivity. However, overexpressing the gene for Rad51, its regulator Brh2, or the Brh2 regulator Dss1 partially restored genotoxin resistance of the lkh1Δ and lkh1Q488② mutants. Deletion of lkh1 in a chk1Δ mutant enabled these double mutant cells to continue to cycle when challenged with hydroxyurea. lkh1Δ and lkh1Q488② mutants were able to complete the meiotic process but exhibited reduced heteroallelic recombination and aberrant chromosome segregation. The observations suggest that Lkh1 serves in some aspect of cell cycle regulation after DNA damage or replication stress and that it also contributes to proper chromosome segregation in meiosis.

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Novel Insights into Chk1 Regulation by Phosphorylation

Cited by 31 publications

References 85 publications

Melanoma LAMP-2C Modulates Tumor Growth and Autophagy

Melanoma LAMP-2C Modulates Tumor Growth and Autophagy

Significant expression of CHK1 and p53 in bladder urothelial carcinoma as potential therapeutic targets and prognosis

LAMMER kinase contributes to genome stability in Ustilago maydis

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