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Mechanical stretch induces mitochondria-dependent apoptosis in neonatal rat cardiomyocytes and G2/M accumulation in cardiac fibroblasts

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Cell Research 2004年第1期14卷 16-26页

作者： Xu Dong LIAO~(1,2), Xiao Hui WANG~1, Hai Jing JIN~1, Lan Ying CHEN~(2,*), Quan CHEN~(1,*) ~1laboratory of apoptosis and cancer biology, State Key laboratory of Biomembrane and Membrane Biotechnology, Chinese Academy of Sciences, Beijing 100080, China. ~2Cardiovascular Institute and Fu Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100037, China. laboratory of apoptosis and cancer biology State Key Laboratory of Biomembrane and Membrane Biotechnology Chinese Academy of Sciences Beijing China Cardiovascular Institute and Fu Wai Hospital Peking Union Medical College and Chinese Academy of Medical Sciences Beijing China

Heart remodeling is associated with the loss of cardiomyocytes and increase of fibrous tissue owing to abnormal mechanical load in a number of heart disease conditions. In present study, a well-described in vitro sustained stretch model was employed to study mechanical stretch-induced responses in both neonatal cardiomyocytes and cardiac fibroblasts. Cardiomyocytes, but not cardiac fibroblasts, underwent mitochondria-dependent apoptosis as evidenced by cytochrome c (cyto c) and Smac/DIABLO release from mitochondria into cytosol accompanied by mitochondrial membrane potential (△ψ_m) reduction, indicative of mitochondrial permeability transition pore (PTP) opening. Cyclosporin A, an inhibitor of PTP, inhibited stretch-induced cyto c release, △ψ_m reduction and apoptosis, suggesting an important role of mitochondrial PTP in stretch-induced apoptosis. The stretch also resulted in increased expression of the pro-apoptotic Bcl-2 family proteins, including Bax and Bad, in cardiomyocytes, but not in fibrobl

关键词： apoptosis mechanical stretch Bcl-2 and its family proteins mitochondria cardiomyocyte.

Remarkably Reduced Expression of FoxO3a in Metaplastic Colorectum, Primary Colorectal cancer and Liver Metastasis

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2013年第2期33卷 205-211页

作者：何乐亚魏欣杜蕾刘鹭徐丰闵江李川陶德定陈佺胡俊波龚建平 Department of Gastrointestinal Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology The laboratory of apoptosis and cancer biology the State Key Laboratory of Biomembrane and Membrane Biotechnology Institute of Zoology Chinese Academy of Sciences

The forkhead family members of transcription factors （FoxOs） are expected to be potential cancer-related drug targets and thus are being extremely studied recently. In the present study, FoxO3a, one major member of this family, was identified to be down-regulated in colorectal cancer through mi- cro-array analysis, which was confirmed by RT-PCR and Western blot in 28 patients. Moreover, immu- nohistochemistry （IHC） showed that the expression levels of FoxO3a were remarkably reduced in 99 cases of primary colorectal cancer, liver metastasis, and even in metaplastic colorectal tissue. IHC also revealed an exclusion of FoxO3a from the nucleus of most cells of tumor-associated tissues. Silencing FoxO3a by siRNA led to elevation of G2-M phase cells. We conclude that the downregulation of FoxO3a may greatly contribute to tumor development, and thus FoxO3a may represent a novel thera- peutic target in colorectal cancer.

关键词： FoxO3a colorectal cancer transcription factor cell cycle arrest target therapy

Down-regulation of DPH2L gene during cellular differentiation/apoptosis:Use of mRNA differential display

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Chinese Science Bulletin 1999年第6期44卷 496-503页

作者： Nicoletta Ferrari Giovanni Levi laboratory of Molecular biology National Institute for Cancer ResearchLaboratory of Molecular Biology National Institute for Cancer Research Genova Italy Genova Italy

To characterize the genes associated with differentiation/apoptosis induced by all-trans retinoic acid (ATRA) in human lung cancer cells, mRNA differential display was employed. Six cDNA fragments have been isolated, and one of them corresponds to a sequence-known gene DPH2L with unknown function, which was first isolated from the critical region of deletion on chromosome 17p13.3 in human ovarian carcinoma, and regarded as a candidate tumor suppressor gene. Results show that DPH2L is a wide expressed gene, and has another major transcript besides the previously reported 2.3 kb transcript. It is proved that the DPH2L gene is dawn-regulated during differentiation or apoptosis in several kinds of cancer cells induced by all-trans retinoic acid and N-(4-hydroxyphenyl) retinamide (4HPR). This may suggest that DPH2L does not play a role as a tumor suppressor gene, on the contrary, its down-regulation may be functionally involved in the transition from cell growth to differentiation or apoptosis.

关键词： mRNA differential display retinoic acids cell differentiation apoptosis tumor suppressor gene.

Neuronal regulated cell death in aging-related neurodegenerative diseases:key pathways and therapeutic potentials

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Neural Regeneration Research 2025年第8期20卷 2245-2263页

作者： Run Song Shiyi Yin Jiannan Wu Junqiang Yan Department of Neurology The First Affiliated HospitalCollege of Clinical Medicine of Henan University of Science and TechnologyLuoyangHenan ProvinceChina Neuromolecular biology laboratory The First Affiliated HospitalCollege of Clinical Medicine of Henan University of Science and TechnologyLuoyangHenan ProvinceChina

Regulated cell death(such as apoptosis,necroptosis,pyroptosis,autophagy,cuproptosis,ferroptosis,disulfidptosis)involves complex signaling pathways and molecular effectors,and has been proven to be an important regulatory mechanism for regulating neuronal aging and ***,excessive activation of regulated cell death may lead to the progression of aging-related *** review summarizes recent advances in the understanding of seven forms of regulated cell death in age-related ***,the newly identified ferroptosis and cuproptosis have been implicated in the risk of cognitive impairment and neurodegenerative *** forms of cell death exacerbate disease progression by promoting inflammation,oxidative stress,and pathological protein *** review also provides an overview of key signaling pathways and crosstalk mechanisms among these regulated cell death forms,with a focus on ferroptosis,cuproptosis,and *** instance,FDX1 directly induces cuproptosis by regulating copper ion valency and dihydrolipoamide S-acetyltransferase aggregation,while copper mediates glutathione peroxidase 4 degradation,enhancing ferroptosis ***,inhibiting the Xc-transport system to prevent ferroptosis can increase disulfide formation and shift the NADP^(+)/NADPH ratio,transitioning ferroptosis to *** insights help to uncover the potential connections among these novel regulated cell death forms and differentiate them from traditional regulated cell death *** conclusion,identifying key targets and their crosstalk points among various regulated cell death pathways may aid in developing specific biomarkers to reverse the aging clock and treat age-related neurodegenerative conditions.

关键词： apoptosis autophagy cuproptosis disulfidptosis ferroptosis necroptosis neurodegenerative disease neurological aging diseases PANoptosis pyroptosis

Endoplasmic reticulum stress and autophagy in cerebral ischemia/reperfusion injury:PERK as a potential target for intervention

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Neural Regeneration Research 2025年第5期20卷 1455-1466页

作者： Ju Zheng Yixin Li Ting Zhang Yanlin Fu Peiyan Long Xiao Gao Zhengwei Wang Zhizhong Guan Xiaolan Qi Wei Hong Yan Xiao Key laboratory of Endemic and Ethnic Diseases Ministry of Education&Key Laboratory of Medical Molecular Biology of Guizhou ProvinceGuizhou Medical UniversityGuiyangGuizhou ProvinceChina Guizhou Center for Disease Control and Prevention GuiyangGuizhou ProvinceChina Department of Histology and Embryology Guizhou Medical UniversityGuiyangGuizhou ProvinceChina Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry GuiyangGuizhou ProvinceChina

Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion *** occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains *** this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion *** found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced ***,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating *** autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion *** from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.

关键词： apoptosis ATF4 autophagy C/EBP homologous protein cerebral ischemia/reperfusion injury eIF2α endoplasmic reticulum stress PERK

Determination of glucose deficiency-induced cell death by mitochondrial ATP generation-driven proton homeostasis

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Journal of Molecular Cell biology 2017年第5期9卷 395-408页

作者： Yanfen Cui Yuanyuan Wang Miao Liu Li Qiu Pan Xing Xin Wang Guoguang Ying Binghui Li laboratory of cancer Cell biology Key Laboratory of Breast Cancer Prevention and Therapy National Clinical Research Center for Cancer Tianjin MedicalUniversity Cancer Institute and Hospital Tianjin 300060 China The First Department of Breast Tumor Key Laboratory of Breast Cancer Prevention and Therapy National Clinical Research Center for Cancer Tianjin MedicalUniversity Cancer Institute and Hospital Tianjin 300060 China

Glucose is one of major nutrients and its catabolism provides energy and/or building bricks for cell proliferation. Glucose deficiency results in cell death. However, the underlying mechanism still remains elusive. By using our recently developed method to monitor real-time cellular apoptosis and necrosis, we show that glucose deprivation can directly elicit necrosis, which is promoted by mito- chondrial impairment, depending on mitochondrial adenosine triphosphate （ATP） generation instead of ATP depletion. We demon- strate that glucose metabolism is the major source to produce protons. Glucose deficiency leads to lack of proton provision while mitochondda[ electron transfer chain continues consuming protons to generate energy, which provokes a compensatory lysosomal proton efflux and resultant increased lysosomal pH. This [ysosomal aikaUnization can trigger apoptosis or necrosis depending on the extent of alkalinization. Taken together, our results build up a metabolic connection between glycolysis, mitochondrion, and iysosome, and reveal an essential role of glucose metabolism in maintaining proton homeostasis to support cell survival.

关键词： glucose deficiency apoptosis necrosis proton homeostasis

The IAP family: endogenous caspase inhibitors with multiple biological activities

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Cell Research 2000年第3期10卷 169-177页

作者： YANG YI LI, XIAO MING LI(laboratory of Immune Cell biology, Division of Basic Sciences, National cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA) Division of Basic Sciences Laboratory of Immune Cell Biology National Cancer Institute National Institutes of Health Bethesda USA

IAPs (inhibitors of apoptosis) are a family of proteins containing one or more characteristic BIR domains. These proteins have multiple biological activities that include binding and inhibiting caspases, regulating cell cycle progression, and modulating receptor-mediated signal transduction. Our recent studies found the IAP family members XIAP and c-IAP1 are ubiquitinated and degraded in proteasomes in response to apoptotic stimuli in T cells, and their degradation appears to be important for T cells to commit to death. In addition to three BIR domains, each of these IAPs also contains a RING finger *** found this region confers ubiquitin protease ligase (E3) activity to IAPs, and is responsible for the auto-ubiquitination and degradation of IAPs after an apoptotic stimulus. Given the factthat IAPs can bind a variety of proteins, such as caspases and TRAFs, it will be of interest to characterize potential substrates of the E3 activity of IAPs and the effects of ubiquitination byIAPs on signal transduction, cell cycle, and apoptosis.

关键词： apoptosis ubiquitination IAP caspase TNF

Phenotype and target-based chemical biology investigations in cancers

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National Science Review 2019年第6期6卷 1111-1127页

作者： Guo-Qiang Chen Ying Xu Shao-Ming Shen Jian Zhang Department of Pathophysiology Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of Medicine (SJTU-SM)

Chemical biology has been attracting a lot of attention because of the key roles of chemical methods and techniques in helping to decipher and manipulate biological systems. Although chemical biology encompasses a broad field, this review will focus on chemical biology aimed at using exogenous chemical probes to interrogate, modify and manipulate biological processes, at the cellular and organismal levels,in a highly controlled and dynamic manner. In this area, many advances have been achieved for cancer biology and therapeutics, from target identification and validation based on active anticancer compounds(forward approaches) to discoveries of anticancer molecules based on some important targets including protein-protein interaction(reverse approaches). Herein we attempt to summarize some recent progresses mainly from China through applying chemical biology approaches to explore molecular mechanisms of carcinogenesis. Additionally, we also outline several new strategies for chemistry to probe cellular activities such as proximity-dependent labeling methods for identifying protein-protein interactions, genetically encoded sensors, and light activating or repressing gene expression system.

关键词： chemical biology chemical compounds target cancer leukemia

CUL4 E3 ligase regulates the proliferation and apoptosis of lung squamous cell carcinoma and small cell lung carcinoma

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cancer biology & Medicine 2020年第2期17卷 357-370页

作者： Ting Li Si Wu Lei Jia Wenfeng Cao Yuan Yao Gang Zhao Hui Li Department of Gastrointestinal cancer biology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin's Clinical Research Center for CancerTianjin 300060China Key laboratory of cancer Immunology and Biotherapy Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin's Clinical Research Center for CancerTianjin 300060China Department of Pathology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin's Clinical Research Center for CancerTianjin 300060China

Objective:The E3 ligase,CRL4,plays diverse roles in different cellular processes,such as DNA damage,transcriptional regulation,cell cycle progression,and cell *** previous study showed that CUL4A and CUL4B had a strong association with tobacco smoking risk in lung squamous cell carcinoma(SCC)and small cell lung carcinoma(SCLC).This study aimed to define the potential mechanism underlying the roles of CUL4A and CUL4B in the development of SCC and ***:We determined the role of CUL4A and CUL4B in the cell cycle and apoptosis of SCC and SCLC,and identified the key apoptosis-related gene involved in the oncogenic activity of CUL4B by Western blot,immunohistochemical staining,flow cytometry,and enzyme inhibition ***:We found that depletion of CUL4A and CUL4B reduced the proliferation of SCC and SCLC ***4Aknockdown but not CUL4Bknockdown arrested cells in Gl phase while upregulating P21 and cU L4Bknockdown promoted cell apoptosis through upregulation o f ***,CUL4B decreased FO X03A expression by activating the ERK signaling pathway and mediating FOXO3A degradation via the ubiquitin-proteasome ***:These results identified the function of E3 ligase CRL4 in regulating SCC and SCLC cell proliferation,which provides a potential strategy for cancer therapy by targeting FOXO3A and the E3 ligase,CRL4.

关键词： Squamous cell lung cancer small cell lung cancer CUL4A CUL4B P21 FOXO3A