Programmed cell death factor 4 (PDCD4), a novel therapy target for metabolic diseases besides cancer

Lu, Kaikai; Chen, Qian; Meng-da, LI; He, Lei; Riaz, Farooq; Zhang, Tianyun; Li, Dongmin

doi:10.1016/j.freeradbiomed.2020.06.016

Cited by 36 publications

(33 citation statements)

References 147 publications

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“…By analogy to its function during cancer metastases, decreases in PDCD4 in neurons would function to enable experience-dependent neuronal growth and remodeling. Dysregulated PDCD4 concentrations have also been reported to underlie a variety of metabolic disorders, including polycystic ovary syndrome, obesity, diabetes, and atherosclerosis, highlighting the critical role PDCD4 plays in regulating gene expression in multiple cell types (Lu et al, 2020). Despite being highly expressed, few studies have examined the function of PDCD4 in neurons (Di Paolo et al, 2020;Li et al, 2020;Narasimhan et al, 2013), and as far as we are aware, no previous study has identified a role for PDCD4 in activity-dependent gene regulation in neurons.…”

Section: Discussionmentioning

confidence: 99%

Neuronal activity promotes nuclear proteasome-mediated degradation of PDCD4 to regulate activity-dependent transcription

Deng

et al. 2021

Preprint

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Activity-dependent gene expression is critical for synapse development and plasticity. To elucidate novel mechanisms linking neuronal activity to changes in transcription, we compared the nuclear proteomes of tetrodotoxin-silenced and bicuculline-stimulated cultured rodent neurons using nuclear-localized APEX2 proximity biotinylation and mass spectrometry. The tumor suppressor protein PDCD4 was enriched in the silenced nuclear proteome, and PDCD4 levels rapidly decreased in the nucleus and cytoplasm of stimulated neurons. The activity-dependent decrease of PDCD4 was prevented by inhibitors of both PKC and proteasome activity and by a phospho-incompetent mutation of Ser71 in the βTRCP ubiquitin ligase-binding motif of PDCD4. We compared the activity-dependent transcriptomes of neurons expressing wildtype or degradation-resistant (S71A) PDCD4. We identified 91 genes as PDCD4 targets at the transcriptional level, including genes encoding proteins critical for synapse formation, remodeling, and transmission. Our findings indicate that regulated degradation of nuclear PDCD4 facilitates activity-dependent transcription in neurons.

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Section: Discussionmentioning

confidence: 99%

Neuronal activity promotes nuclear proteasome-mediated degradation of PDCD4 to regulate activity-dependent transcription

Deng

et al. 2021

Preprint

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“…Decreased PDCD4 expression was observed in various tumors, such as lung cancer, colorectal cancer, breast cancer, hepatocellular carcinoma, and glioblastoma [19][30] [31]. Some pro-apoptotic drugs (such as ionomycin), antineoplastic drugs (such as retinoic acid receptor agonist), or cytokines (including IL-12 and TGF-β1) can stimulate PDCD4 expression [18] [19] Considering its pivotal functions in regulating cellular apoptosis, the potential roles of PDCD4 during neuronal injury has gradually attracted attention. Chronic restraint stress increased PDCD4 expression in mice hippocampus by decreasing the mTORC1-mediated proteasomes degradation [32].…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms that regulating PDCD4 expression during in ammation remain unclear, but its involvement in oncology may provide some clues. PDCD4 expression is reportedly regulated at different levels [18] [19]. The epigenetic silence by promoter methylation and some transcription factors such as FOXO and v-myb directly regulate the Pdcd4 expression at the transcriptional level [18] [19].…”

Section: Discussionmentioning

confidence: 99%

“…Based on its pro-apoptotic and cell-cycle inhibiting activity, intensive efforts have been focusing on its role as a tumor suppressor [19] [20]. PDCD4 exerts its antineoplastic effects by promoting cellular apoptosis and inhibiting malignant transformation, cellular proliferation, invasion, and metastasis [19] [20] [21] Mechanistically, PDCD4 binds to eIF4A/E to inhibit the RNA helicase activity or directly interacts with the target mRNAs to block protein translation [18] [19]. PDCD4 can also combine with certain cytoplasmic proteins, or interact with some transcription factors and thus modulate the target gene transcription [18] [19].…”

Section: Introductionmentioning

confidence: 99%

“…Besides the tumor-suppressive activity, PDCD4 is also widely expressed in immune cells and closely participates in in ammatory responses, but its role during in ammation is still uncertain. The available con icting evidence showed the opposite pro-in ammatory or anti-in ammatory effects of PDCD4 under different experimental conditions [18] [19]. For example, PDCD4 de ciency protected mice against dietinduced obesity, in ammation in white adipose tissue, and insulin resistance via restoring LXR-α expression [22].…”

Section: Introductionmentioning

confidence: 99%

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PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation

Chen

Lü

Duan

et al. 2021

Preprint

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Neuroinflammation and neuron injury are common features of the central nervous system (CNS) diseases. It will be of great significance to identify their shared regulatory mechanisms and explore the potential therapeutic targets. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases, but its expression and biological function during CNS neuroinflammation remain unclear. In the present study, utilizing the lipopolysaccharide (LPS)-induced neuroinflammation model on mice, we first reported an elevated expression of PDCD4 in both injured neurons and activated microglia of the inflamed mice brain. A similar change of PDCD4 expression was observed in the in vitro microglial activation model. Silencing PDCD4 by shRNA significantly inhibited the phosphorylation of MAPKs (p38, ERK, and JNK), prevented the phosphorylation and nuclear transportation of NF-κB p65, and thus attenuated the LPS-induced microglial inflammatory activation. Interestingly, LPS also required the MAPKs/NF-κB signaling activation to boost PDCD4 expression in microglia, and thus form a positive loop. Moreover, a persistent elevation of PDCD4 expression was detected in the H2O2-induced neuronal oxidative damage model. Knocking down PDCD4 significantly inhibited the expression of pro-apoptotic protein BAX, suggesting the pro-apoptotic activity of PDCD4 in the neuron. Taken together, our data indicated that PDCD4 may serve as a hub regulatory molecule that simultaneously promotes both the microglial inflammatory activation and the oxidative stress-induced neuronal apoptosis within CNS. The microglial PDCD4/MAPKs/NF-κB positive feedback loop may exaggerate the vicious cycle of neuroinflammation and neuronal injury, and thus may become potential therapeutic targets for neuroinflammatory diseases.

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Programmed cell death 4: A novel player in the pathogenesis of polycystic ovary syndrome

Zarezadeh,

Abbasi,

Aboutalebi Vand Beilankouhi

et al. 2023

Cell Biochemistry & Function

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Polycystic ovary syndrome (PCOS) is a pathological condition recognized by menstrual cycle irregularities, androgen excess, and polycystic ovarian morphology, affecting a significant proportion of women of childbearing age and accounting for the most prevalent cause of anovulatory sterility. In addition, PCOS is frequently accompanied by metabolic and endocrine disturbances such as obesity, dyslipidemia, insulin resistance, and hyperinsulinemia, indicating the multiplicity of mechanisms implicated in the progression of PCOS. However, the exact pathogenesis of PCOS is yet to be elucidated. Programmed cell death 4 (PDCD4) is a ubiquitously expressed protein that contributes to the regulation of various cellular processes, including gene expression, cell cycle progression, proliferation, and apoptosis. Despite some disparities concerning its exact cellular effects, PDCD4 is generally characterized as a protein that inhibits cell cycle progression and proliferation and instead drives the cell into apoptosis. The apoptosis of granulosa cells (GCs) is speculated to take a major part in the occurrence and progression of PCOS by ceasing antral follicle development and compromising oocyte competence. Given the possible involvement of GC apoptosis in the progression of PCOS, as well as the contribution of PDCD4 to the regulation of cell apoptosis and the development of metabolic diseases, the current review aimed to discuss whether or how PDCD4 can play a role in the pathogenesis of PCOS by affecting GC apoptosis.

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Programmed cell death factor 4 (PDCD4), a novel therapy target for metabolic diseases besides cancer

Cited by 36 publications

References 147 publications

Neuronal activity promotes nuclear proteasome-mediated degradation of PDCD4 to regulate activity-dependent transcription

Neuronal activity promotes nuclear proteasome-mediated degradation of PDCD4 to regulate activity-dependent transcription

PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation

Programmed cell death 4: A novel player in the pathogenesis of polycystic ovary syndrome

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Programmed cell death factor 4 (PDCD4), a novel therapy target for metabolic diseases besides cancer

Cited by 36 publications

References 147 publications

Neuronal activity promotes nuclear proteasome-mediated degradation of PDCD4 to regulate activity-dependent transcription

Neuronal activity promotes nuclear proteasome-mediated degradation of PDCD4 to regulate activity-dependent transcription

PDCD4-MAPKs-NF-κB positive loop&nbsp;simultaneously&nbsp;promotes&nbsp;microglia activation and neuron apoptosis&nbsp;during&nbsp;neuroinflammation

Programmed cell death 4: A novel player in the pathogenesis of polycystic ovary syndrome

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PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation