A Conserved Mechanism for Binding of p53 DNA-Binding Domain and Anti-Apoptotic Bcl-2 Family Proteins

Lee, Dong Hwa; Ha, Ji-Hyang; Kim, Yul; Jang, Mi; Jean, Park， Sung; Yoon, Ho Sup; Kim, Eun‐Hee; Bae, Kwang‐Hee; Park, Byoung Chul; Park, Sung Goo; Yi, Gwan‐Su; Chi, Seung‐Wook

doi:10.14348/molcells.2014.0001

Cited by 28 publications

(28 citation statements)

References 45 publications

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“…The interactions between BCL-w and poorly characterized members of the BCL-2 family, BFK 20 and BOP 21 have also been reported. Moreover, α1/2 and α5/6 loops of BCL-w can associate with p53 through p53 DNA-binding domain, which contributes to transcription-independent regulation of cell death 22 . BCL-w also interacts with BH3-like domain of Beclin-1, an autophagy-related protein 23 .…”

Section: Introductionmentioning

confidence: 99%

BCL-w: apoptotic and non-apoptotic role in health and disease

Hartman

Czyż

2020

Cell Death Dis

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The BCL-2 family of proteins integrates signals that trigger either cell survival or apoptosis. The balance between prosurvival and pro-apoptotic proteins is important for tissue development and homeostasis, while impaired apoptosis contributes to several pathologies and can be a barrier against effective treatment. BCL-w is an anti-apoptotic protein that shares a sequence similarity with BCL-X L , and exhibits a high conformational flexibility. BCL-w level is controlled by a number of signaling pathways, and the repertoire of transcriptional regulators largely depends on the cellular and developmental context. As only a few disease-relevant genetic alterations of BCL2L2 have been identified, increased levels of BCL-w might be a consequence of abnormal activation of signaling cascades involved in the regulation of BCL-w expression. In addition, BCL-w transcript is a target of a plethora of miRNAs. Besides its originally recognized pro-survival function during spermatogenesis, BCL-w has been envisaged in different types of normal and diseased cells as an anti-apoptotic protein. BCL-w contributes to survival of senescent and drug-resistant cells. Its non-apoptotic role in the promotion of cell migration and invasion has also been elucidated. Growing evidence indicates that a high BCL-w level can be therapeutically relevant in neurodegenerative disorders, neuron dysfunctions and after small intestinal resection, whereas BCL-w inhibition can be beneficial for cancer patients. Although several drugs and natural compounds can bi-directionally affect BCL-w level, agents that selectively target BCL-w are not yet available. This review discusses current knowledge on the role of BCL-w in health, non-cancerous diseases and cancer.

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Section: Introductionmentioning

confidence: 99%

BCL-w: apoptotic and non-apoptotic role in health and disease

Hartman

Czyż

2020

Cell Death Dis

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“…The association between afatinib and the Bcl-2 protein family was further investigated. The Bcl-2 protein family comprises pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) proteins that modulate permeabilization of the mitochondrial outer membrane and caspase activation in the control of apoptosis (16). The present study indicates that afatinib treatment upregulates the pro-apoptotic protein Bax and downregulates the anti-apoptotic protein Bcl-2.…”

Section: Discussionmentioning

confidence: 50%

Afatinib inhibits proliferation and invasion and promotes apoptosis of the T24 bladder cancer cell line

Tang

Zhang

Fan

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Afatinib is a highly selective, irreversible inhibitor of the epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2). Although preclinical and clinical studies have indicated that afatinib has antitumor activity and clinical efficacy in non-small cell lung carcinoma, head and neck squamous cell carcinoma and breast cancer, there are few studies investigating its inhibitory effect on human bladder carcinoma cells. In this study, the antitumor effect of afatinib was investigated on the T24 bladder cancer cell line. The T24 bladder cancer cell line was treated with afatinib at various concentrations (0, 1, 5, 10 and 20 µmol/l). MTT assay was used to estimate the proliferation of the T24 cells; flow cytometric analysis was used to estimate the effect of afatinib on T24 cell apoptosis; cell invasion ability was assessed by a Transwell invasion assay; and western blot analysis was used to detect the expression of Bcl-2, Bax, Akt, extracellular-signal-regulated kinase (ERK)1/2, matrix metalloproteinase (MMP)-2 and MMP-9. The MTT assay demonstrated that afatinib inhibited the proliferation of T24 cells in a dose-and time-dependent manner. Flow cytometric analysis revealed that the cell apoptosis rate increased as the concentration of afatinib increased. The cell invasion assay indicated that afatinib treatment significantly inhibited the invasive behavior of T24 cells in a dose-dependent manner. Western blot analysis showed that with increasing afatinib concentrations, Bcl-2, phosphorylated (p)-ERK1/2, p-Akt, MMP-2 and MMP-9 expression levels were significantly decreased, whereas total (t)-ERK1/2 and t-Akt expression levels remained basically unchanged, and Bax expression levels were greatly increased. The results indicate that afatinib inhibits the proliferation and invasion of T24 cells in vitro and induces the apoptosis of these cells by inhibiting the EGFR signaling network.

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“…The p53 gene, encoding a transcriptional factor, may induce apoptosis of tumor cells and serve as a tumor suppressor gene. The Bcl-2 protein, a member of the Bcl-2 family, may inhibit the cell apoptosis in a number of types of cancer ( 47 ). In the present study, expression of JNK2 and the phosphorylation protein p-JNK2 were upregulated by the overexpression of miR-146a, which indicated that JNK2 may be activated by miR-146a.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of miR‑146a increases cisplatin sensitivity of the non‑small cell lung cancer A549 cell line by targeting JNK‑2

Pang¹,

Lü²,

Huang³

et al. 2017

Oncol Lett

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The aim of the present study was to investigate the effects of microRNA (miR-)146a on the cisplatin sensitivity of the non-small cell lung cancer (NSCLC) A549 cell line and study the underlying molecular mechanism. The differences in expression of miRNAs between A549 and A549/cisplatin (A549/DDP) cells were determined, and miR-146a was selected to study its effect on cisplatin sensitivity of A549/DDP cells. miR-146a mimic and inhibitor transient transfection systems were constructed using vectors, and A549/DDP cells were infected with miR-146a mimic and inhibitor to investigate growth, apoptosis and migration. The directed target of miR-146a was determined and the underlying molecular mechanism was validated in the present study. The results of the present study demonstrated that miR-146a was downregulated in NSCLC A549/DDP cells, compared with A549 cells. The overexpression of miR-146a induced apoptosis and inhibited the growth and invasion of A549/DDP cells, which resulted in increased cisplatin sensitivity in NSCLC cells. The JNK2 gene was determined as the direct target of miR-146a, and may be activated by the overexpression of miR-146a. Additionally, JNK2 activated the expression of p53 and inhibited B cell lymphoma 2. The upregulation of miR-146a increased cisplatin sensitivity of the A549 cell line by targeting JNK2, which may provide a novel method for treating NSCLC cisplatin resistance.

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A Conserved Mechanism for Binding of p53 DNA-Binding Domain and Anti-Apoptotic Bcl-2 Family Proteins

Cited by 28 publications

References 45 publications

BCL-w: apoptotic and non-apoptotic role in health and disease

BCL-w: apoptotic and non-apoptotic role in health and disease

Afatinib inhibits proliferation and invasion and promotes apoptosis of the T24 bladder cancer cell line

Upregulation of miR‑146a increases cisplatin sensitivity of the non‑small cell lung cancer A549 cell line by targeting JNK‑2

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