Adaptive Basal Phosphorylation of eIF2α Is Responsible for Resistance to Cellular Stress–Induced Cell Death in <i>Pten</i>-Null Hepatocytes

Zeng, Ni; Li, Yang; He, Liyun; Xu, Xiaoling; Galicia, Vivian; Deng, Chu‐Xia; Stiles, Bangyan L.

doi:10.1158/1541-7786.mcr-11-0299

Cited by 29 publications

(33 citation statements)

References 35 publications

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“…11A). We have shown previously that the Pten-null hepatocytes are capable of forming colonies on soft agar (20). Here, we found that inhibition of ERR␣ with siRNA significantly inhibits the ability of Pten-null hepatocytes to form colonies (Fig.…”

Section: Knockdown Of Err␣ Attenuates Colony Forming Potential In Ptesupporting

confidence: 62%

“…Western Blot and Immunoprecipitation-Cell lysate preparation and immunoblot analysis were described previously (20). Antibodies against PTEN, p-AKT, CREB, and p-CREB were purchased from Cell Signaling Technology.…”

Section: Animals-pten Loxp/loxp ;Alb-crementioning

confidence: 99%

“…In addition, activity of thioredoxin reductase is also increased (123.4 Ϯ 10.3 versus 91.8 Ϯ 11.2 M/min/mg, n ϭ 4) in the Pten null livers, further indicating higher oxidative stress conditions. To determine whether the production of ROS is a direct consequence of PTEN loss or is secondary due to other cellular process changes occurring in the liver, we down-regulated PTEN in immortalized hepatocytes (20) established from the control mice. Inhibition of PTEN with two independent shRNAs led to increased ROS production in the hepatocytes (Fig.…”

Section: Levels Of Reactive Oxygen Species In Hepatocytes Arementioning

confidence: 99%

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Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) Signaling Regulates Mitochondrial Biogenesis and Respiration via Estrogen-related Receptor α (ERRα)

Yang

Zeng

et al. 2013

Journal of Biological Chemistry

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Background: Aberrant PTEN/PI3K signaling and mitochondrial abnormalities are commonly associated with cancer. Results: PTEN loss and activation of PI3K/protein kinase B up-regulate ERR␣, increase mitochondrial mass, and induce a metabolic pattern similar to the "Warburg effect." Conclusion: PTEN/PI3K signaling controls mitochondrial mass and function by regulating ERR␣ through the AKT/CREB axis. Significance: This study establishes a novel link between oncogenic signaling and dysregulated mitochondrial metabolism.

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Section: Knockdown Of Err␣ Attenuates Colony Forming Potential In Ptesupporting

confidence: 62%

Section: Animals-pten Loxp/loxp ;Alb-crementioning

confidence: 99%

Section: Levels Of Reactive Oxygen Species In Hepatocytes Arementioning

confidence: 99%

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Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) Signaling Regulates Mitochondrial Biogenesis and Respiration via Estrogen-related Receptor α (ERRα)

Yang

Zeng

et al. 2013

Journal of Biological Chemistry

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“…PfeIF2α phospohorylation level in different erythrocytic stages of clinical isolates post longer time ART treatment requires further investigation. In higher eukaryotic cells, basal phosphorylation of eIF2α is responsible for resistance to stress induced cell death (Zeng et al, 2011). Phosphorylation of PfeIF2α may be responsible for resistance to ARTs.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency

Zhang

Gállego-Delgado

Fernández-Arias

et al. 2017

Cell Host & Microbe

116

157

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Summary Artemisinin and its derivatives (ARTs) are frontline antimalarial drugs. However, ART monotherapy is associated with a high frequency of recrudescent infection, resulting in treatment failure. A subset of parasites is thought to undergo ART-induced latency, but the mechanisms remain unknown. Here we report that ART treatment results in phosphorylation of the parasite eukaryotic initiation factor-2α (eIF2α), leading to repression of general translation and latency induction. Enhanced phosphorylated eIF2α correlates with high rates of recrudescence following ART, and inhibiting eIF2α dephosphorylation renders parasites less sensitive to ART treatment. ART-induced eIF2α phosphorylation is mediated by the Plasmodium eIF2α kinase, PK4. Overexpression of a PK4 dominant-negative or pharmacological inhibition of PK4 blocks parasites from entering latency and abolishes recrudescence after ART treatment of infected mice. These results show that translational control underlies ART-induced latency and that interference with this stress response may resolve the clinical problem of recrudescent infection.

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“…Mouse hepatocyte cell lines used in this study were established from Pten control and null mice (23, 24). mEF cells used has been reported before (25).…”

Section: Methodsmentioning

confidence: 99%

Crosstalk of LKB1‐regulated and PTEN‐regulated signals in liver morphogenesis and tumor development in mice

Jia

Medina

Liu

et al. 2017

Hepatology Communications

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Liver kinase B 1 (LKB1 or STK11) and PTEN (phosphatase and tensin homologue deleted on chromosome 10) are two tumor suppressors that regulate the mTOR signaling pathway. Deletion studies show that loss of either Lkb1 (Lkb+/−) or Pten (PtenloxP/loxP; Alb-Cre+) leads to liver injury and development of hepatocarcinoma. In this study, we investigated the crosstalk of LKB1 and PTEN loss during tumorigenesis and liver development. We show here that haplo-insufficiency of Lkb1 in the liver leads to advanced tumor development in the Pten null mice (PtenloxP/loxP; LkbloxP/+; Alb-Cre+). Our analysis shows that LKB1 and PTEN interacted with each other in their regulation of fatty acid synthase as well as p21 expression. The combined loss of LKB1 and PTEN (PtenloxP/loxP; LkbloxP/loxP; Alb-Cre+) also led to the inability to form zonal structures in the liver. The lack of metabolic zonal structures is consistent with the inability of the livers to store glycogen as well as elevated plasma bilirubin and alanine aminotransferase (ALT), indicative of liver dysfunction. These structural and functional defects are associated with cytoplasm distribution of a canalicular membrane protein MRP2 (multidrug resistant protein 2) which is responsible for clearing bilirubin. This observed regulation of MRP2 by LKB1 likely contributed to the lack of cellular polarity and the early lethality phenotype associated with homozygous loss of Lkb1 alone or in combination with Pten. Finally, Pten deletion does not rescue the precocious ductal plate formation reported for Lkb1 deleted livers. Conclusion: Our study dissected the functional and molecular crosstalk of PTEN and LKB1 and elucidate key molecular targets for such interaction.

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Adaptive Basal Phosphorylation of eIF2α Is Responsible for Resistance to Cellular Stress–Induced Cell Death in Pten-Null Hepatocytes

Cited by 29 publications

References 35 publications

Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) Signaling Regulates Mitochondrial Biogenesis and Respiration via Estrogen-related Receptor α (ERRα)

Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) Signaling Regulates Mitochondrial Biogenesis and Respiration via Estrogen-related Receptor α (ERRα)

Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency

Crosstalk of LKB1‐regulated and PTEN‐regulated signals in liver morphogenesis and tumor development in mice

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