Mdm2 promotes Cdc25C protein degradation and delays cell cycle progression through the G2/M phase

Giono, Luciana E.; Resnick‐Silverman, Lois; Carvajal, Luis A.; Clair, Selvon St.; Manfredi, James J.

doi:10.1038/onc.2017.254

Cited by 52 publications

(38 citation statements)

References 80 publications

(100 reference statements)

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“…Cdc25C shuttles in and out of the nucleus continuously, just like cyclin B1. Cdc25C will not cause premature mitosis before cyclin B1 overexpress (Karlsson et al, 1999) and cdc25C is a member of the cyclin-dependent kinases of cell cycle-related CDKs (Giono et al, 2017). In the present study, we found that SB induced cell cycle arrest at G2/M phase and reduced the protein expressions of cdc25C, CDK1, and cyclin B1 in cervical cancer cells, which may be the mechanism of action underlying the SB-inhibited cervical cancer cell proliferation.…”

Section: Discussionsupporting

confidence: 57%

“…In the progression of the cell cycle, members of the CDK family and the partner cyclinproteins are the primary mediators controlling the point of entry into mitosis in cells (Jones et al, 2018). Cyclin B1/CDK1 kinase translocating rapidly from the cytoplasm to the nucleus is the critical target of G2 into mitosis transition (Giono et al, 2017). CDK1 promotes the DNA replicative synthesis and regulates the balance of cell cycle, thus coordinating and maintaining genomic stability, which is vital for cell survival (Liao et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer

You

et al. 2020

Front. Pharmacol.

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Cervical cancer is the fourth leading cancer type and the second most common gynecological malignancy among women worldwide. Silibinin (SB), a chief bioactive natural polyphenolic flavonoid of Silybum marianum L., has been used clinically for its hepatocyte protective effects. It also has anticancer effects via the induction of apoptosis and cell cycle arrest. However, the effects of SB on cervical cancer cells through mitochondrial fission have not been studied. Here, we showed that SB markedly suppressed cervical cell proliferation by inducing G2/M cell cycle arrest via the activation of dynamin-related protein 1 (Drp1), which in turn mediated the mitochondrial fission dysfunction both in vitro and in vivo. SB decreased the ATP content, mitochondrial membrane potential, and mtDNA copy number, as well as reduced the reactive oxygen species levels in cervical cells. Furthermore, SB induced excessive mitochondrial fragmentation and reduced tubule formation. Further study showed that knockdown of Drp1 abolished the SB-induced G2/M cell cycle arrest in cervical cancer cells by inhibiting the mitochondrial fission pathway. More importantly, SB inhibited Hela cell growth in vivo model. In conclusion, we are the first to demonstrate that SB induces cervical cancer cell G2/M cell cycle arrest by activating Drp1-dependent mitochondrial fission dysfunction. This study suggests the strategy of inducing Drp1-dependent mitochondrial fission for cervical cancer prevention and treatment.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer

You

et al. 2020

Front. Pharmacol.

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“…Neurofibromatosis Type 2 Protein (NF2) is involved in cell cycle regulation, although it has not been shown to have a direct effect on the cell cycle [36]. Other proteins, including GADD45α, The Aurora Kinase A (AURKA) [37], and Mouse double minute 2 homolog (MDM2) [38], have been shown to regulate cell cycle progression at the G2/M phase. Interestingly, it was reported that induction of GADD45α increased its association with cyclin-dependent kinase 1 (CDK1; also known as cell division cycle protein 2 homolog) and forced it to dissociate from cyclin B1/CDK1 complexes.…”

Section: Discussionmentioning

confidence: 99%

ER Stress Induces Cell Cycle Arrest at the G2/M Phase Through eIF2α Phosphorylation and GADD45α

Lee

Hokinson

Park

et al. 2019

IJMS

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Endoplasmic reticulum (ER) stress is known to influence various cellular functions, including cell cycle progression. Although it is well known how ER stress inhibits cell cycle progression at the G1 phase, the molecular mechanism underlying how ER stress induces G2/M cell cycle arrest remains largely unknown. In this study, we found that ER stress and subsequent induction of the UPR led to cell cycle arrest at the G2/M phase by reducing the amount of cyclin B1. Pharmacological inhibition of the IRE1α or ATF6α signaling did not affect ER stress-induced cell cycle arrest at the G2/M phase. However, when the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) phosphorylation was genetically abrogated, the cell cycle progressed without arresting at the G2/M phase after ER stress. GEO database analysis showed that growth arrest and DNA-damage-inducible protein α (Gadd45α) were induced in an eIF2a phosphorylation-dependent manner, which was confirmed in this study. Knockdown of GADD45α abrogated cell cycle arrest at the G2/M phase upon ER stress. Finally, the cell death caused by ER stress significantly reduced when GADD45α expression was knocked down. In conclusion, GADD45α is a key mediator of ER stress-induced growth arrest via regulation of the G2/M transition and cell death through the eIF2α signaling pathway.

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“…But all the noscapine analogues except 4 and 1 decreased the expression of Cdc25C protein, which is necessary for the progression of cell cycle through the G2/M phase. Cdc25C activity inhibition is pivotal for the G2 checkpoint and has been shown that decrease in Cdc25C expression causes cell cycle arrest at G2/M phase . These results demonstrate that noscapine analogues 6 e – g and 6 j result in G2/M phase arrest as indicated by the levels of cell‐cycle regulators cyclin B1, CDK1, Cdc25C.…”

Section: Resultsmentioning

confidence: 99%

Anticancer Potential of N‐Sulfonyl Noscapinoids: Synthesis and Evaluation

et al. 2020

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Noscapine is an alkaloid with a basic phthalideisoquinoline moiety and is well recognized as an antitussive drug. It is obtained from opium poppy Papaver somniferum and demonstrates a rather safe toxicity profile in vitro. Recent studies found noscapine and its analogues to have anticancer activity against mammalian cancer cell lines by modulating microtubule assembly. In the present study, we report the synthesis and evaluation of cytotoxicity of a series of N‐sulfonyl noscapinoids 6 a–n obtained by reaction of nornoscapine with various aryl/heteroaryl sulfonyl chlorides. To assess the antiproliferative activity of the novel derivatives 6 a–n, SRB assay was performed in four different human cancer cell lines, MIAPaCa‐2 (pancreatic), HeLa (cervical), SK−N−SH (neuroblastoma) and DU145 (prostate cancer). The study identified four compounds 6 e–g and 6 j ability to arrest cell‐cycle at the G2/M phase and cytotoxic potential against the human pancreatic cancer cell line MIAPaCa‐2. We observed that these compounds 6 e–g and 6 j induce microtubule depolymerisation and cause cell cycle arrest at the G2/M phase thereby resulting in caspase‐3 and PARP activation leading to cell death. In silico molecular docking studies of these compounds showed non‐covalent interactions like Van der Waals and hydrogen‐bonding with tubulin protein and with good binding energy.

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Mdm2 promotes Cdc25C protein degradation and delays cell cycle progression through the G2/M phase

Cited by 52 publications

References 80 publications

Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer

Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer

ER Stress Induces Cell Cycle Arrest at the G2/M Phase Through eIF2α Phosphorylation and GADD45α

Anticancer Potential of N‐Sulfonyl Noscapinoids: Synthesis and Evaluation

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