PP4 deficiency leads to DNA replication stress that impairs immunoglobulin class switch efficiency

Chen, Mingyu; Hsu, Wei-Chan; Hsu, Shu-Shong; Yang, Yu-Shao; Chuang, Tsung‐Hsien; Lin, Wen‐Jye; Tan, Tse‐Hua; Y, Su

doi:10.1038/s41418-018-0199-z

Cited by 11 publications

(4 citation statements)

References 64 publications

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“…PDE4D, as a hydrolase of cAMP, inhibits the activity of downstream PKA by reducing the concentration of cAMP. PKA is a key kinase activated by AMPK ( Chen et al, 2019 ). Furthermore, PDE4D inhibition by AAV9-shPDE4D injection reversed the inhibitory effect of miR-223-3p inhibitor on AMPK phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-223-3p Protect Against Radiation-Induced Cardiac Toxicity by Alleviating Myocardial Oxidative Stress and Programmed Cell Death via Targeting the AMPK Pathway

Zhang

Deng

et al. 2022

Front. Cell Dev. Biol.

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Objectives: Radiotherapy improves the survival rate of cancer patients, yet it also involves some inevitable complications. Radiation-induced heart disease (RIHD) is one of the most serious complications, especially the radiotherapy of thoracic tumors, which is characterized by cardiac oxidative stress disorder and programmed cell death. At present, there is no effective treatment strategy for RIHD; in addition, it cannot be reversed when it progresses. This study aims to explore the role and potential mechanism of microRNA-223-3p (miR-223-3p) in RIHD.Methods: Mice were injected with miR-223-3p mimic, inhibitor, or their respective controls in the tail vein and received a single dose of 20 Gy whole-heart irradiation (WHI) for 16 weeks after 3 days to construct a RIHD mouse model. To inhibit adenosine monophosphate activated protein kinase (AMPK) or phosphodiesterase 4D (PDE4D), compound C (CompC) and AAV9-shPDE4D were used.Results: WHI treatment significantly inhibited the expression of miR-223-3p in the hearts; furthermore, the levels of miR-223-3p decreased in a radiation time-dependent manner. miR-223-3p mimic significantly relieved, while miR-223-3p inhibitor aggravated apoptosis, oxidative damage, and cardiac dysfunction in RIHD mice. In addition, we found that miR-223-3p mimic improves WHI-induced myocardial injury by activating AMPK and that the inhibition of AMPK by CompC completely blocks these protective effects of miR-223-3p mimic. Further studies found that miR-223-3p lowers the protein levels of PDE4D and inhibiting PDE4D by AAV9-shPDE4D blocks the WHI-induced myocardial injury mediated by miR-223-3p inhibitor.Conclusion: miR-223-3p ameliorates WHI-induced RIHD through anti-oxidant and anti-programmed cell death mechanisms via activating AMPK by PDE4D regulation. miR-223-3p mimic exhibits potential value in the treatment of RIHD.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-223-3p Protect Against Radiation-Induced Cardiac Toxicity by Alleviating Myocardial Oxidative Stress and Programmed Cell Death via Targeting the AMPK Pathway

Zhang

Deng

et al. 2022

Front. Cell Dev. Biol.

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“…Moreover, LPS treatment in combination with IL-4 induced Chk1 phosphorylation as well as DNA damage responses in B cells, although this may be due to the induction of CSR which involves double-stranded DNA breaks [35]. Therefore, bacterial LPS is a potential agent that affects DNA replication and induces replication checkpoint [36–37]. Moreover, heat-induced Chk1 activation, which depended on Rad9, Rad17, TopBP1 and Claspin, was reported in HeLa cells and chicken B lymphoma DT40 cells [38].…”

Section: Introductionmentioning

confidence: 99%

Claspin-dependent and -independent Chk1 activation by a panel of biological stresses

Hsiao

Yang

Masai

2022

Preprint

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Replication stress has been suggested to be an ultimate trigger of carcinogenesis. Oncogenic signal, such as overexpression of CyclinE, has been shown to induce replication stress. Here, we show that various biological stresses, including heat, oxidative stress, osmotic stress, LPS, hypoxia, and arsenate induce activation of Chk1, a key effector kinase for replication checkpoint. Some of these stresses indeed reduce the fork rate, inhibiting DNA replication. Analyses of Chk1 activation in the cell population with western analyses showed that Chk1 activation by these stresses is largely dependent on Claspin. On the other hand, single cell analyses with Fucci cells indicated that while Chk1 activation during S phase is dependent on Claspin, that in G1 is mostly independent of Claspin. We propose that various biological stresses activate Chk1 either directly by stalling DNA replication fork or by some other mechanism that does not involve replication inhibition. The former pathway predominantly occurs in S phase and depends on Claspin, while the latter pathway, which may occur throughout the cell cycle, is largely independent of Claspin.Our findings provide evidence for novel links between replication stress checkpoint and other biological stresses and points to the presence of unknown mechanisms of Chk1 activation in mammalian cells.

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“…Several cellular signaling routes, including NF-kappaB JNK pathway, apoptotic signaling and the target of rapamycin (TOR) pathways appear to be regulated by PPP4 (ref. [32][33][34][35][36][37]. However, the physiological role of PPP4 in mammalian gonads remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Protein Phosphatase 4 (PPP4) Prevents Female Reprogramming in the Mouse Testis After Sex Determination and Protects Male Fertility

Han

Dong

Lei

et al. 2021

Preprint

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Background: Impairment of lineage specification and function of gonadal somatic cells can lead to disorders of sexual development (DSDs) and fertility defects in humans. However, little is known about the function of protein phosphatases in testis development. Results: We showed that protein phosphatase 4 (PPP4) could maintain SOX9 expression in Sertoli cells and play an essential role in Sertoli cell lineage maintenance and male fertility. Conditional deletion of Ppp4c, a PPP4 catalytic subunit gene, caused the reprogramming of Sertoli cells to granulosa-like cells postnatally by inducing ectopic expression of FOXL2, which in turn led to testicular BTB structure damage, germ cell loss and ultimate testis to ovary-like gland transformation. Conclusion: Reprogramming of Sertoli cells due to absence of PPP4 may help explain the etiology of disorders of sexual differentiation and male infertility.

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PP4 deficiency leads to DNA replication stress that impairs immunoglobulin class switch efficiency

Cited by 11 publications

References 64 publications

MicroRNA-223-3p Protect Against Radiation-Induced Cardiac Toxicity by Alleviating Myocardial Oxidative Stress and Programmed Cell Death via Targeting the AMPK Pathway

MicroRNA-223-3p Protect Against Radiation-Induced Cardiac Toxicity by Alleviating Myocardial Oxidative Stress and Programmed Cell Death via Targeting the AMPK Pathway

Claspin-dependent and -independent Chk1 activation by a panel of biological stresses

Protein Phosphatase 4 (PPP4) Prevents Female Reprogramming in the Mouse Testis After Sex Determination and Protects Male Fertility

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