Raf-1 Kinase Inhibitory Protein (RKIP) Mediates Ethanol-induced Sensitization of Secretagogue Signaling in Pancreatic Acinar Cells

Kim, Sung Ok; Ives, Kirk L.; Wang, Xiaofu; Davey, Robert A.; Chao, Celia; Hellmich, Mark R.

doi:10.1074/jbc.m112.367656

Cited by 8 publications

(6 citation statements)

References 64 publications

(59 reference statements)

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“…The association between ethanol (EtOH) consumption and pancreatitis has been well‐established. In an elegant study, EtOH has been shown to induce the sensitization of secretagogue Ca 2+ signaling in pancreatic aciner cells and to induce subsequent adverse reactions, resulting in pancreatitis (Kim et al, 2012c). Kim et al showed that EtOH induced the PKC‐dependent phosphorylation of RKIP.…”

Section: Clinical Significance Of Rkip and Prkip Perturbationmentioning

confidence: 99%

“…These data highlight RKIP as a pivotal mediator of EtOH cytotoxic effect on pancreatic aciner cells. Therefore, the inhibition of RKIP expression may be utilized as a therapeutic treatment strategy to prevent alcohol‐related pancreatitis, which, if left untreated may eventually develop into cancer (Kim et al, 2012c). This study also suggests an important role for p‐RKIP in Ca 2+ homeostasis, which may be significantly relevant to other diseases associated with Ca 2+ perturbations.…”

Section: Clinical Significance Of Rkip and Prkip Perturbationmentioning

confidence: 99%

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RKIP: Much more than Raf Kinase inhibitory protein

Al-Mulla

Bitar

Taqi

et al. 2013

Journal Cellular Physiology

115

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From its discovery as a phosphatidylethanolamine-binding protein in bovine brain to its designation as a physiological inhibitor of Raf kinase protein, RKIP has emerged as a critical molecule for maintaining subdued, well-orchestrated cellular responses to stimuli. The disruption of RKIP in a wide range of pathologies, including cancer, Alzheimer's disease, and pancreatitis, makes it an exciting target for individualized therapy and disease-specific interventions. This review attempts to highlight recent advances in the RKIP field underscoring its potential role as a master modulator of many pivotal intracellular signaling cascades that control cellular growth, motility, apoptosis, genomic integrity, and therapeutic resistance. Specific biological and functional niches are highlighted to focus future research towards an enhanced understanding of the multiple roles of RKIP in health and disease.

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Section: Clinical Significance Of Rkip and Prkip Perturbationmentioning

confidence: 99%

Section: Clinical Significance Of Rkip and Prkip Perturbationmentioning

confidence: 99%

RKIP: Much more than Raf Kinase inhibitory protein

Al-Mulla

Bitar

Taqi

et al. 2013

Journal Cellular Physiology

115

View full text Add to dashboard Cite

show abstract

“…HCT116 cells were infected at a multiplicity of infection (MOI) of 3 with hexadimethrine bromide (8 μg/mL). Transduced cells were selected and maintained in McCoy's 5A media supplemented with 10% (vol/vol) FBS and puromycin (2 μg/mL) (45). To overexpress CBS in NCM356 cells, gene transfer was accomplished using an adenovirus at a MOI of 10, with a green fluorescent protein-expressing adenovirus used as a control (46).…”

Section: Methodsmentioning

confidence: 99%

Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer

Szabó¹,

Coletta²,

Chao³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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637

693

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The physiological functions of hydrogen sulfide (H 2 S) include vasorelaxation, stimulation of cellular bioenergetics, and promotion of angiogenesis. Analysis of human colon cancer biopsies and patient-matched normal margin mucosa revealed the selective upregulation of the H 2 S-producing enzyme cystathionine-β-synthase (CBS) in colon cancer, resulting in an increased rate of H 2 S production. Similarly, colon cancer-derived epithelial cell lines (HCT116, HT-29, LoVo) exhibited selective CBS up-regulation and increased H 2 S production, compared with the nonmalignant colonic mucosa cells, NCM356. CBS localized to the cytosol, as well as the mitochondrial outer membrane. ShRNA-mediated silencing of CBS or its pharmacological inhibition with aminooxyacetic acid reduced HCT116 cell proliferation, migration, and invasion; reduced endothelial cell migration in tumor/endothelial cell cocultures; and suppressed mitochondrial function (oxygen consumption, ATP turnover, and respiratory reserve capacity), as well as glycolysis. Treatment of nude mice with aminooxyacetic acid attenuated the growth of patientderived colon cancer xenografts and reduced tumor blood flow. Similarly, CBS silencing of the tumor cells decreased xenograft growth and suppressed neovessel density, suggesting a role for endogenous H 2 S in tumor angiogenesis. In contrast to CBS, silencing of cystathionine-γ-lyase (the expression of which was unchanged in colon cancer) did not affect tumor growth or bioenergetics. In conclusion, H 2 S produced from CBS serves to (i) maintain colon cancer cellular bioenergetics, thereby supporting tumor growth and proliferation, and (ii) promote angiogenesis and vasorelaxation, consequently providing the tumor with blood and nutritients. The current findings identify CBS-derived H 2 S as a tumor growth factor and anticancer drug target.

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“…Under certain inflammatory conditions, including chronic pancreatitis 13 and metabolic disorders, 14 phosphorylation of RKIP occurs through protein kinase C (PKC), phosphatidyl inositol-3 kinase (PI3K) or other pathways. When induced by protein PKC, phosphorylation occurs at the Ser153 residue, inducing a conformational change in the ligand binding pocket.…”

Section: Rkip Contribution To Pro-inflammatory Signaling (Table 2)mentioning

confidence: 99%

Interactions of RKIP with Inflammatory Signaling Pathways

Zhao

Wenzel

2014

Crit Rev Oncog

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The inflammatory response plays an important role in host defense and maintenance of homeostasis, while imbalances in these responses can also lead to pathologic disease processes. Emerging data show that RKIP interacts with multiple signaling molecules which may potentiate multiple functions during inflammatory processes. This chapter will review the interaction of RKIP with both the MAPK and NF-κB pathways in relation to chronic inflammatory diseases. In these settings, it can both inhibit inflammatory pathways as well contribute to pro-inflammatory signaling, often depending on the interactions with multiple proteins and perhaps lipids. The interactions of RKIP with proteins, phospholipids, fatty acids and their enzymes, thus, could play a substantial role in diseases like asthma and diabetes. Targeting interactions of RKP with these pathways could lead to novel approaches to treatment.

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Raf-1 Kinase Inhibitory Protein (RKIP) Mediates Ethanol-induced Sensitization of Secretagogue Signaling in Pancreatic Acinar Cells

Cited by 8 publications

References 64 publications

RKIP: Much more than Raf Kinase inhibitory protein

RKIP: Much more than Raf Kinase inhibitory protein

Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer

Interactions of RKIP with Inflammatory Signaling Pathways

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