Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions

Matsuhashi, Sachiko; Manirujjaman, M.; Hamajima, Hiroshi; Ozaki, Iwata

doi:10.3390/ijms20092304

Cited by 106 publications

(126 citation statements)

References 104 publications

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“…TPA (12-O-tetradecanoylphorbol-13-acetate), a potent stimulator of protein kinase C (PKC), also induces the phosphorylation and degradation of PDCD4 protein. The TPA-activated PKCδ and PKCε signaling pathways phosphorylate PDCD4, leading to its degradation by the proteasome system in Huh7 hepatocellular carcinoma cells [18,25,26]. During the investigation of PDCD4 degradation mechanisms, we found that the proteasome inhibitor MG132 slightly upregulated the PDCD4 protein levels in Huh7 cells [26].…”

Section: Introductionmentioning

confidence: 88%

“…The PDCD4 mRNA expression is silenced by methylation at the 5 CpG island of the PDCD4 promotor region [17]. However, PDCD4 gene mutations have not been reported and the expression is mostly controlled post transcriptionally at translation and protein degradation levels [18]. MicroRNAs (miRNAs), which are endogenous non-coding small RNAs, bind to the 3 -UTR region of the transcript and induce either translational suppression or degradation of the mRNAs.…”

Section: Introductionmentioning

confidence: 99%

“…As 71S and 76S in the degron are phosphorylated, PDCD4 protein is ubiquitinated by SCF βTRCP ubiquitin ligase and degraded by the proteasome system. The phosphorylation of the upstream serine 67 (67S) triggers the phosphorylation of 71S and 76S [18,24]. TPA (12-O-tetradecanoylphorbol-13-acetate), a potent stimulator of protein kinase C (PKC), also induces the phosphorylation and degradation of PDCD4 protein.…”

Section: Introductionmentioning

confidence: 99%

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Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy

Manirujjaman

Ozaki

Murata

et al. 2020

Cells

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PDCD4 (programmed cell death 4) is a tumor suppressor that plays a crucial role in multiple cellular functions, such as the control of protein synthesis and transcriptional control of some genes, the inhibition of cancer invasion and metastasis. The expression of this protein is controlled by synthesis, such as via transcription and translation, and degradation by the ubiquitin-proteasome system. The mitogens, known as tumor promotors, EGF (epidermal growth factor) and TPA (12-O-tetradecanoylphorbol-13-acetate) stimulate the degradation of PDCD4 protein. However, the whole picture of PDCD4 degradation mechanisms is still unclear, we therefore investigated the relationship between PDCD4 and autophagy. The proteasome inhibitor MG132 and the autophagy inhibitor bafilomycin A1 were found to upregulate the PDCD4 levels. PDCD4 protein levels increased synergistically in the presence of both inhibitors. Knockdown of p62/SQSTM1 (sequestosome-1), a polyubiquitin binding partner, also upregulated the PDCD4 levels. P62 and LC3 (microtubule-associated protein 1A/1B-light chain 3)-II were co-immunoprecipitated by an anti-PDCD4 antibody. Colocalization particles of PDCD4, p62 and the autophagosome marker LC3 were observed and the colocalization areas increased in the presence of autophagy and/or proteasome inhibitor(s) in Huh7 cells. In ATG (autophagy related) 5-deficient Huh7 cells in which autophagy was impaired, the PDCD4 levels were increased at the basal levels and upregulated in the presence of autophagy inhibitors. Based on the above findings, we concluded that after phosphorylation in the degron and ubiquitination, PDCD4 is degraded by both the proteasome and autophagy systems.

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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy

Manirujjaman

Ozaki

Murata

et al. 2020

Cells

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“…Programmed cell death protein 4 (PDCD4) is a tumor suppressor responsible for the inhibition of cell growth, tumor invasion, metastasis, or induction of apoptosis [213]. It is localized in the nucleus of proliferating cells and binds to the eukaryotic initiation factor-4A (eIF4A) or eukaryotic translation initiation factor 4 G (eIF4G), inhibiting translation [214,215].…”

Section: Downregulation Of Programmed Cell Death Proteinmentioning

confidence: 99%

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

Baj

Korona-Głowniak

Forma

et al. 2020

Cells

116

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Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting half of the world's population. Approximately 20% of the infected patients develop gastric ulcers or neoplastic changes in the gastric stroma. An infection also leads to the progression of epithelial-mesenchymal transition within gastric tissue, increasing the probability of gastric cancer development. This paper aims to review the role of H. pylori and its virulence factors in epithelial-mesenchymal transition associated with malignant transformation within the gastric stroma. The reviewed factors included: CagA (cytotoxin-associated gene A) along with induction of cancer stem-cell properties and interaction with YAP (Yes-associated protein pathway), tumor necrosis factor α-inducing protein, Lpp20 lipoprotein, Afadin protein, penicillin-binding protein 1A, microRNA-29a-3p, programmed cell death protein 4, lysosomal-associated protein transmembrane 4β, cancer-associated fibroblasts, heparin-binding epidermal growth factor (HB-EGF), matrix metalloproteinase-7 (MMP-7), and cancer stem cells (CSCs). The review summarizes the most recent findings, providing insight into potential molecular targets and new treatment strategies for gastric cancer.

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“…38 PDCD4 is an anti-carcinoma gene related to cell cycle and apoptosis. 39 Many researches had pointed out it could be used as a therapeutic target for various carcinomas. 40 Studies also pointed out that PDCD4 was low expressed in various carcinoma tissues such as gastric carcinoma and so on.…”

Section: Discussionmentioning

confidence: 99%

<p>Matrine Restrains Cell Growth and Metastasis by Up-Regulating LINC00472 in Bladder Carcinoma</p>

Wang

2020

CMAR

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These authors contributed equally to this workPurpose: Bladder Carcinoma (BC) is a malignant carcinoma with a high incidence in masculinity. We preliminarily researched the efficacy and mechanism of matrine (MAT) in T24 and 5637 cells. Patients and Methods: CCK-8, flow cytometry, migration and invasion means were adopted to detect cell viability, apoptosis, migratory and invasive potentials. Moreover, LINC00472 expression was changed via transfection assays and was tested by RT-qPCR. Western blot was used for investigating the levels of CyclinD1, p53, Bcl-2, Bax, pro-Caspase-3, Cleaved-Caspase-3, β-actin, programmed cell death protein 4 (PDCD4) and relate-proteins of cell pathways. Tumor volume and weight were tested via animal experiments. Results: MAT could not affect the growth of SV-HUC-1 cell but MAT promoted tumor cell apoptosis but restrained viability, invasion and migration. Furthermore, LINC00472 was prominently low expressed in BC tissues. MAT positively regulated LINC00472 and transfection with si-00472 could partly reverse the efficacies of MAT. Moreover, MAT enhanced PDCD4 expression by up-regulating LINC00472. Besides, we discovered MAT elevated PTEN but restrained PI3K/AKT proteins. Finally, tumor volume and weight were declined by MAT in vivo via up-regulating LINC00472. Conclusion: MAT restrained cell growth and metastasis but promoted PDCD4 expression by up-regulating LINC00472 via restraining PTEN/PI3K/AKT pathway in BC.

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Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions

Cited by 106 publications

References 104 publications

Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy

Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

<p>Matrine Restrains Cell Growth and Metastasis by Up-Regulating LINC00472 in Bladder Carcinoma</p>

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