Chk1 and Wee1 control genotoxic-stress induced G2–M arrest in melanoma cells

Vera, Julio; Raatz, Yvonne; Kottek, Tina; Bhattacharya, Animesh; Simon, Jan C.; Kunz, Manfred

doi:10.1016/j.cellsig.2015.01.020

Cited by 35 publications

(23 citation statements)

References 43 publications

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“…In dividing eukaryotic cells, CDC2 dephosphorylation is essential for mitotic progression . Before mitosis, CDC2 activity is suppressed through the Wee1‐mediated inhibitory phosphorylation of Tyr15 and Thr14 residues of CDC2 . Hence, we investigated whether RO3280 hindered CDC2 dephosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Targeted inhibition of Polo‐like kinase 1 by a novel small‐molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells

Zhang

Kong

2016

J Cellular Molecular Medi

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Bladder cancer is a common cancer with particularly high recurrence after transurethral resection. Despite improvements in neoadjuvant chemotherapy, the outcome of patients with advanced bladder cancer has changed very little. In this study, the anti‐tumour activities of a novel Polo‐like kinase 1 (PLK1) inhibitor (RO3280) was evaluated in vitro and in vivo in the bladder carcinoma cell lines 5637 and T24. MTT assays, colony‐formation assays, flow cytometry, cell morphological analysis and trypan blue exclusion assays were used to examine the proliferation, cell cycle distribution and apoptosis of bladder carcinoma cells with or without RO3280 treatment. Moreover, real‐time RT‐PCR and Western blotting were used to detect the expressions of genes that are related to these cellular processes. Our results showed that RO3280 inhibited cell growth and cell cycle progression, increased Wee1 expression and cell division cycle protein 2 phosphorylation. In addition, RO3280 induced mitotic catastrophe and apoptosis, increased cleaved PARP (poly ADP‐ribose polymerase) and caspase‐3, and decreased BubR1 expression. The in vivo assay revealed that RO3280 retarded bladder cancer xenograft growth in a nude mouse model. Although further laboratory and pre‐clinical investigations are needed to corroborate these data, our demonstration of bladder cancer growth inhibition and dissemination using a pharmacological inhibitor of PLK1 provides new opportunities for future therapeutic intervention.

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Section: Resultsmentioning

confidence: 99%

Targeted inhibition of Polo‐like kinase 1 by a novel small‐molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells

Zhang

Kong

2016

J Cellular Molecular Medi

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“…WEE1 is another checkpoint kinase that mediates G2/M cell cycle arrest through phosphorylation of CHK1, which inhibits mitotic transition (97, 98). Functional analysis identified WEE1 as an important survival factor in p53-mutant head and neck squamous cell carcinomas (99, 100).…”

Section: Targeting Pathways That Are Critical For Survival Of P53 Mutmentioning

confidence: 99%

Molecularly targeted therapies for p53-mutant cancers

Zhao

Tahaney

Mazumdar

et al. 2017

Cell. Mol. Life Sci.

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The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.

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“…A recent study that aimed to define the significance of HUWE1 to mammalian protein quality control demonstrated a putative relationship between HUWE1 and the replication stress response protein Chk1 . Chk1 is a serine/threonine kinase that plays an essential role in preserving genome integrity in cells experiencing impaired replication or genotoxic stress , and delays late origin firing until replication has resumed at stalled forks . In addition to modulating replication stress, Chk1 also has important functions within an unperturbed cell cycle: Chk1 participates in genome surveillance , prevents premature mitotic entry , and regulates the spindle assembly checkpoint .…”

Section: Introductionmentioning

confidence: 99%

Direct regulation of Chk1 protein stability by E3 ubiquitin ligase HUWE1

et al. 2019

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The HECT E3 ubiquitin ligase HUWE1 is required for a wide array of important functions in cell biology. Although HUWE1 is known to play a role in DNA damage signaling, the mechanism(s) that underlie this function remain elusive. HUWE1 regulates effectors of DNA replication and genotoxic stress tolerance. However, the loss of HUWE1 can also result in the accrual of significant endogenous DNA damage due to insufficient remediation of replication stress induced by an overabundance of key substrates. We discovered that HUWE1 depletion leads to a significant increase in levels of the single-strand break effector kinase Chk1, independent of the DNA damage response, activation of apical DNA damage repair (DDR) signaling kinases (ATM and ATR), and the tumor suppressor p53. We also identified multiple lysine residues on Chk1 that are polyubiquitinated by HUWE1 in vitro, many of which are within the kinase domain. HUWE1 knockdown also markedly prolonged the protein half-life of Chk1 in steadystate conditions and resulted in greater stabilization of Chk1 protein than depletion of Cul4A, an E3 ubiquitin ligase previously described to control Chk1 abundance. Moreover, prolonged replication stress induced by hydroxyurea or camptothecin resulted in a reduction of Chk1 protein levels, which was rescued by HUWE1 knockdown. Our study indicates that HUWE1 plays a significant role in the regulation of the DDR signaling pathway by directly modulating the abundance of Chk1 protein.

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Chk1 and Wee1 control genotoxic-stress induced G2–M arrest in melanoma cells

Cited by 35 publications

References 43 publications

Targeted inhibition of Polo‐like kinase 1 by a novel small‐molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells

Targeted inhibition of Polo‐like kinase 1 by a novel small‐molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells

Molecularly targeted therapies for p53-mutant cancers

Direct regulation of Chk1 protein stability by E3 ubiquitin ligase HUWE1

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