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Full-Text Articles in Cell Biology

A Small Peptide Antagonist Of The Fas Receptor Inhibits Neuroinflammation And Prevents Axon Degeneration And Retinal Ganglion Cell Death In An Inducible Mouse Model Of Glaucoma, Anitha Krishnan, Andrew J. Kocab, David N. Zacks, Ann Marshak-Rothstein, Meredith Gregory-Ksander Sep 2019

A Small Peptide Antagonist Of The Fas Receptor Inhibits Neuroinflammation And Prevents Axon Degeneration And Retinal Ganglion Cell Death In An Inducible Mouse Model Of Glaucoma, Anitha Krishnan, Andrew J. Kocab, David N. Zacks, Ann Marshak-Rothstein, Meredith Gregory-Ksander

Open Access Articles

BACKGROUND: Glaucoma is a complex, multifactorial disease where apoptosis, microglia activation, and inflammation have been linked to the death of retinal ganglion cells (RGCs) and axon degeneration. We demonstrated previously that FasL-Fas signaling was required for axon degeneration and death of RGCs in chronic and inducible mouse models of glaucoma and that Fas activation triggered RGC apoptosis, glial activation, and inflammation. Here, we investigated whether targeting the Fas receptor with a small peptide antagonist, ONL1204, has anti-inflammatory and neuroprotective effects in a microbead-induced mouse model of glaucoma.

METHODS: Intracameral injection of microbeads was used to elevate intraocular pressure (IOP) in ...


Expression Of Mitochondrial Membrane-Linked Sab Determines Severity Of Sex-Dependent Acute Liver Injury, Sanda Win, Robert W. M. Min, Christopher Q. Chen, Jun Zhang, Yibu Chen, Meng Li, Ayako Suzuki, Manal F. Abdelmalek, Ying Wang, Mariam Aghajan, Filbert W. M. Aung, Anna Mae Diehl, Roger J. Davis, Tin A. Than, Neil Kaplowitz Sep 2019

Expression Of Mitochondrial Membrane-Linked Sab Determines Severity Of Sex-Dependent Acute Liver Injury, Sanda Win, Robert W. M. Min, Christopher Q. Chen, Jun Zhang, Yibu Chen, Meng Li, Ayako Suzuki, Manal F. Abdelmalek, Ying Wang, Mariam Aghajan, Filbert W. M. Aung, Anna Mae Diehl, Roger J. Davis, Tin A. Than, Neil Kaplowitz

University of Massachusetts Medical School Faculty Publications

SAB is an outer membrane docking protein for JNK mediated impaired mitochondrial function. Deletion of Sab in hepatocytes inhibits sustained JNK activation and cell death. Current work demonstrated that increasing SAB enhanced the severity of APAP liver injury. Female mice were resistant to liver injury and exhibited markedly decreased hepatic SAB protein expression versus males. The mechanism of SAB repression involved a pathway from ERalpha to p53 expression which induced miR34a-5p. miR34a-5p targeted the Sab mRNA coding region, repressing SAB expression. Fulvestrant or p53 knockdown decreased miR34a-5p and increased SAB in females leading to increased injury from APAP and TNF ...


Atf6alpha Impacts Cell Number By Influencing Survival, Death And Proliferation, Rohit B. Sharma, Jarin T. Snyder, Laura C. Alonso Sep 2019

Atf6alpha Impacts Cell Number By Influencing Survival, Death And Proliferation, Rohit B. Sharma, Jarin T. Snyder, Laura C. Alonso

Open Access Articles

BACKGROUND: A growing body of literature suggests the cell-intrinsic activity of Atf6alpha during ER stress responses has implications for tissue cell number during growth and development, as well as in adult biology and tumorigenesis [1]. This concept is important, linking the cellular processes of secretory protein synthesis and endoplasmic reticulum stress response with functional tissue capacity and organ size. However, the field contains conflicting observations, especially notable in secretory cell types like the pancreatic beta cell.

SCOPE OF REVIEW: Here we summarize current knowledge of the basic biology of Atf6alpha, along with the pleiotropic roles Atf6alpha plays in cell life ...


Activation Of The Apoptotic Pathway During Prolonged Prometaphase Blocks Daughter Cell Proliferation, Yumi Uetake, Greenfield Sluder Nov 2018

Activation Of The Apoptotic Pathway During Prolonged Prometaphase Blocks Daughter Cell Proliferation, Yumi Uetake, Greenfield Sluder

Radiology Publications and Presentations

When untransformed human cells spend >1.5 hr. in prometaphase under standard culture conditions, all daughters arrest in G1 despite normal division of their mothers. We investigate what happens during prolonged prometaphase that leads to daughter cell arrest in the absence of DNA damage. We find that progressive loss of anti-apoptotic MCL-1 activity and oxidative stress act in concert to partially activate the apoptosis pathway resulting in the delayed death of some daughters and senescence for the rest. At physiological oxygen levels, longer prometaphase durations are needed for all daughters to arrest. Partial activation of apoptosis during prolonged prometaphase leads ...


Jnk Promotes Epithelial Cell Anoikis By Transcriptional And Post-Translational Regulation Of Bh3-Only Proteins, Nomeda Girnius, Roger J. Davis Nov 2017

Jnk Promotes Epithelial Cell Anoikis By Transcriptional And Post-Translational Regulation Of Bh3-Only Proteins, Nomeda Girnius, Roger J. Davis

UMass Metabolic Network Publications

Developmental morphogenesis, tissue injury, and oncogenic transformation can cause the detachment of epithelial cells. These cells are eliminated by a specialized form of apoptosis (anoikis). While the processes that contribute to this form of cell death have been studied, the underlying mechanisms remain unclear. Here, we tested the role of the cJUN NH2-terminal kinase (JNK) signaling pathway using murine models with compound JNK deficiency in mammary and kidney epithelial cells. These studies demonstrated that JNK is required for efficient anoikis in vitro and in vivo. Moreover, JNK-promoted anoikis required pro-apoptotic members of the BCL2 family of proteins. We show that ...


Regulation Of Ripk1 Activation By Tak1-Mediated Phosphorylation Dictates Apoptosis And Necroptosis, Jiefei Geng, Yasushi Ito, Linyu Shi, Palak Amin, Jiachen Chu, Amanda Tomie Ouchida, Adnan Kasim Mookhtiar, Heng Zhao, Daichao Xu, Bing Shan, Ayaz Najafov, Guangping Gao, Shizuo Akira, Junying Yuan Aug 2017

Regulation Of Ripk1 Activation By Tak1-Mediated Phosphorylation Dictates Apoptosis And Necroptosis, Jiefei Geng, Yasushi Ito, Linyu Shi, Palak Amin, Jiachen Chu, Amanda Tomie Ouchida, Adnan Kasim Mookhtiar, Heng Zhao, Daichao Xu, Bing Shan, Ayaz Najafov, Guangping Gao, Shizuo Akira, Junying Yuan

Open Access Articles

Stimulation of TNFR1 by TNFalpha can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFalpha-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFalpha leads to RIPK1-independent apoptosis when NF-kappaB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA ...


Killers Creating New Life: Caspases Drive Apoptosis-Induced Proliferation In Tissue Repair And Disease, Caitlin E. Fogarty, Andreas Bergmann Aug 2017

Killers Creating New Life: Caspases Drive Apoptosis-Induced Proliferation In Tissue Repair And Disease, Caitlin E. Fogarty, Andreas Bergmann

Open Access Articles

Apoptosis is a carefully orchestrated and tightly controlled form of cell death, conserved across metazoans. As the executioners of apoptotic cell death, cysteine-dependent aspartate-directed proteases (caspases) are critical drivers of this cellular disassembly. Early studies of genetically programmed cell death demonstrated that the selective activation of caspases induces apoptosis and the precise elimination of excess cells, thereby sculpting structures and refining tissues. However, over the past decade there has been a fundamental shift in our understanding of the roles of caspases during cell death-a shift precipitated by the revelation that apoptotic cells actively engage with their surrounding environment throughout the ...


Differential Involvement Of The Microtubule Cytoskeleton In Insulin Receptor Substrate 1 (Irs-1) And Irs-2 Signaling To Akt Determines The Response To Microtubule Disruption In Breast Carcinoma Cells, Jose Mercado-Matos, Jennifer L. Clark, Andrew J. Piper, Jenny Janusis, Leslie M. Shaw May 2017

Differential Involvement Of The Microtubule Cytoskeleton In Insulin Receptor Substrate 1 (Irs-1) And Irs-2 Signaling To Akt Determines The Response To Microtubule Disruption In Breast Carcinoma Cells, Jose Mercado-Matos, Jennifer L. Clark, Andrew J. Piper, Jenny Janusis, Leslie M. Shaw

UMass Metabolic Network Publications

The insulin receptor substrate (IRS) proteins serve as essential signaling intermediates for the activation of PI3K by both the insulin-like growth factor 1 receptor (IGF-1R) and its close family member, the insulin receptor (IR). Although IRS-1 and IRS-2 share significant homology, they regulate distinct cellular responses downstream of these receptors and play divergent roles in breast cancer. To investigate the mechanism by which signaling through IRS-1 and IRS-2 results in differential outcomes, we assessed the involvement of the microtubule cytoskeleton in IRS-dependent signaling. Treatment with drugs that either stabilize or disrupt microtubules reveal that an intact microtubule cytoskeleton contributes to ...


Genetic Disruption Of Oncogenic Kras Sensitizes Lung Cancer Cells To Fas Receptor-Mediated Apoptosis, Haiwei Mou, Jill Moore, Sunil K. Malonia, Yingxiang Li, Deniz M. Ozata, Soren Hough, Chun-Qing Song, Jordan L. Smith, Andrew H. Fischer, Zhiping Weng, Michael R. Green, Wen Xue Apr 2017

Genetic Disruption Of Oncogenic Kras Sensitizes Lung Cancer Cells To Fas Receptor-Mediated Apoptosis, Haiwei Mou, Jill Moore, Sunil K. Malonia, Yingxiang Li, Deniz M. Ozata, Soren Hough, Chun-Qing Song, Jordan L. Smith, Andrew H. Fischer, Zhiping Weng, Michael R. Green, Wen Xue

Program in Bioinformatics and Integrative Biology Publications and Presentations

Genetic lesions that activate KRAS account for approximately 30% of the 1.6 million annual cases of lung cancer. Despite clinical need, KRAS is still undruggable using traditional small-molecule drugs/inhibitors. When oncogenic Kras is suppressed by RNA interference, tumors initially regress but eventually recur and proliferate despite suppression of Kras Here, we show that tumor cells can survive knockout of oncogenic Kras, indicating the existence of Kras-independent survival pathways. Thus, even if clinical KRAS inhibitors were available, resistance would remain an obstacle to treatment. Kras-independent cancer cells exhibit decreased colony formation in vitro but retain the ability to form ...


The Beneficial Role Of Extracellular Reactive Oxygen Species In Apoptosis-Induced Compensatory Proliferation, Neha Diwanji, Andreas Bergmann Aug 2016

The Beneficial Role Of Extracellular Reactive Oxygen Species In Apoptosis-Induced Compensatory Proliferation, Neha Diwanji, Andreas Bergmann

Molecular, Cell and Cancer Biology Publications

Apoptosis-induced proliferation (AiP) maintains tissue homeostasis following massive stress-induced cell death. During this phenomenon, dying cells induce proliferation of the surviving cells to compensate for the tissue loss, and thus restore organ size. Along with wound healing and tissue regeneration, AiP also contributes to tumor repopulation following radiation or chemotherapy. There are several models of AiP. Using an "undead" AiP model that causes hyperplastic overgrowth of Drosophila epithelial tissue, we recently demonstrated that extracellular reactive oxygen species (eROS) are produced by undead epithelial cells, and are necessary for inducing AiP and overgrowth. Furthermore, hemocytes, the Drosophila blood cells, are seen ...


Er Stress In Temozolomide-Treated Glioblastomas Interferes With Dna Repair And Induces Apoptosis, Jessica L. Weatherbee, Jean-Louis Kraus, Alonzo H. Ross Jun 2016

Er Stress In Temozolomide-Treated Glioblastomas Interferes With Dna Repair And Induces Apoptosis, Jessica L. Weatherbee, Jean-Louis Kraus, Alonzo H. Ross

Open Access Articles

Glioblastoma multiforme (GBM) is a deadly grade IV brain tumor. Radiation in combination with temozolomide (TMZ), the current chemotherapeutic for GBMs, only provides 12-14 months survival post diagnosis. Because GBMs are dependent on both activation of the DNA damage pathway and the endoplasmic reticulum (ER) stress response, we asked if a novel ER stress inducing agent, JLK1486, increases the efficacy of TMZ. We found that the combination of TMZ+JLK1486 resulted in decreased proliferation in a panel of adherent GBM cells lines and reduced secondary sphere formation in non-adherent and primary lines. Decreased proliferation correlated with increased cell death due ...


Transcriptional Activation Of Follistatin By Nrf2 Protects Pulmonary Epithelial Cells Against Silica Nanoparticle-Induced Oxidative Stress, Chen Lin, Xinyuan Zhao, Desen Sun, Lingda Zhang, Wenpan Fang, Tingjia Zhu, Qiang Wang, Botao Liu, Saisai Wei, Guangdi Chen, Zhengping Xu, Xiangwei Gao Feb 2016

Transcriptional Activation Of Follistatin By Nrf2 Protects Pulmonary Epithelial Cells Against Silica Nanoparticle-Induced Oxidative Stress, Chen Lin, Xinyuan Zhao, Desen Sun, Lingda Zhang, Wenpan Fang, Tingjia Zhu, Qiang Wang, Botao Liu, Saisai Wei, Guangdi Chen, Zhengping Xu, Xiangwei Gao

Open Access Articles

Silica nanoparticles (SiO2 NPs) cause oxidative stress in respiratory system. Meanwhile, human cells launch adaptive responses to overcome SiO2 NP toxicity. However, besides a few examples, the regulation of SiO2 NP-responsive proteins and their functions in SiO2 NP response remain largely unknown. In this study, we demonstrated that SiO2 NP induced the expression of follistatin (FST), a stress responsive gene, in mouse lung tissue as well as in human lung epithelial cells (A549). The levels of Ac-H3(K9/18) and H3K4me2, two active gene markers, at FST promoter region were significantly increased during SiO2 NP treatment. The induction of FST ...


A Novel Autophagy Regulatory Mechanism That Functions During Programmed Cell Death: A Dissertation, Tsun-Kai Chang Sep 2013

A Novel Autophagy Regulatory Mechanism That Functions During Programmed Cell Death: A Dissertation, Tsun-Kai Chang

GSBS Dissertations and Theses

Autophagy is a cellular process that delivers cytoplasmic materials for degradation by the lysosomes. Autophagy-related (Atg) genes were identified in yeast genetic screens for vehicle formation under stress conditions, and Atg genes are conserved from yeast to human. When cells or animals are under stress, autophagy is induced and Atg8 (LC3 in mammal) is activated by E1 activating enzyme Atg7. Atg8-containing membranes form and surround cargos, close and mature to become the autophagosomes. Autophagosomes fuse with lysosomes, and cargos are degraded by lysosomal enzymes to sustain cell viability. Therefore, autophagy is most frequently considered to function in cell survival. Whether ...


Combined Experimental And Computational Analysis Of Dna Damage Signaling Reveals Context-Dependent Roles For Erk In Apoptosis And G1/S Arrest After Genotoxic Stress, Andrea R. Tentner, Michael J. Lee, Gerry J. Ostheimer, Leona D. Samson, Douglas A. Lauffenburger, Michael B. Yaffe Jan 2012

Combined Experimental And Computational Analysis Of Dna Damage Signaling Reveals Context-Dependent Roles For Erk In Apoptosis And G1/S Arrest After Genotoxic Stress, Andrea R. Tentner, Michael J. Lee, Gerry J. Ostheimer, Leona D. Samson, Douglas A. Lauffenburger, Michael B. Yaffe

Program in Systems Biology Publications and Presentations

Following DNA damage, cells display complex multi-pathway signaling dynamics that connect cell-cycle arrest and DNA repair in G1, S, or G2/M phase with phenotypic fate decisions made between survival, cell-cycle re-entry and proliferation, permanent cell-cycle arrest, or cell death. How these phenotypic fate decisions are determined remains poorly understood, but must derive from integrating genotoxic stress signals together with inputs from the local microenvironment. To investigate this in a systematic manner, we undertook a quantitative time-resolved cell signaling and phenotypic response study in U2OS cells receiving doxorubicin-induced DNA damage in the presence or absence of TNFalpha co-treatment; we measured ...


Functional Analysis Of Ing1 And Ing4 In Cell Growth And Tumorigenesis: A Dissertation, Andrew H. Coles May 2008

Functional Analysis Of Ing1 And Ing4 In Cell Growth And Tumorigenesis: A Dissertation, Andrew H. Coles

GSBS Dissertations and Theses

The five member Inhibitor of Growth (ING) gene family has been proposed to participate in the regulation of cell growth, DNA repair, inflammation, chromatin remodeling, and tumor suppression. All ING proteins contain a PHD motif implicated in binding to methylated histones and are components of large chromatin remodeling complexes containing histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes, suggesting a role for ING proteins in regulating gene transcription. Additionally, forced overexpression studies performed in vitro have indicated that several ING proteins can interact with the p53 tumor suppressor protein and/or the NF-кB protein complex. Since these two proteins play ...