Meta-analysis of microarray data: The case of imatinib resistance in chronic myelogenous leukemia

Burguillo, F.J.; Martín, J; Barrera, Inmaculada

doi:10.1016/j.compbiolchem.2010.06.003

Cited by 12 publications

(11 citation statements)

References 37 publications

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“…ATF6␣ and PDIA5 have been associated with cell survival and chemoresistance in different tumor types (21,22). Using leukemia as a model, we sought to determine the role of this newly identified axis in chemoresistance, a well-defined ER stress inducer.…”

Section: Resultsmentioning

confidence: 99%

“…In this context, and to follow up on our initial aim, we investigated the relevance of this axis to cancer cell phenotypes. Interestingly, PDIA5 was found to be overexpressed in numerous cancers and to be part of a predictive signature of tumor cell resistance to chemotherapy (21,22); however, the mechanisms underlying this observation remain poorly understood. Since ATF6␣ had previously been associated with tumor cell dormancy (11), a hallmark of chemotherapy resistance, we investigated the role of the PDIA5/ATF6␣ axis in cancer cell resistance to imatinib.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Endoplasmic Reticulum Stress-Activated Transcription Factor ATF6α Requires the Disulfide Isomerase PDIA5 To Modulate Chemoresistance

Higa

Taouji

Lhomond

et al. 2014

Molecular and Cellular Biology

179

156

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e ATF6␣, a membrane-anchored transcription factor from the endoplasmic reticulum (ER) that modulates the cellular response to stress as an effector of the unfolded-protein response (UPR), is a key player in the development of tumors of different origin. ATF6␣ activation has been linked to oncogenic transformation and tumor maintenance; however, the mechanism(s) underlying this phenomenon remains elusive. Here, using a phenotypic small interfering RNA (siRNA) screening, we identified a novel role for ATF6␣ in chemoresistance and defined the protein disulfide isomerase A5 (PDIA5) as necessary for ATF6␣ activation upon ER stress. PDIA5 contributed to disulfide bond rearrangement in ATF6␣ under stress conditions, thereby leading to ATF6␣ export from the ER and activation of its target genes. Further analysis of the mechanism demonstrated that PDIA5 promotes ATF6␣ packaging into coat protein complex II (COPII) vesicles and that the PDIA5/ATF6␣ activation loop is essential to confer chemoresistance on cancer cells. Genetic and pharmacological inhibition of the PDIA5/ATF6␣ axis restored sensitivity to the drug treatment. This work defines the mechanisms underlying the role of ATF6␣ activation in carcinogenesis and chemoresistance; furthermore, it identifies PDIA5 as a key regulator ATF6␣-mediated cellular functions in cancer. P rotein folding in the endoplasmic reticulum (ER) can be particularly affected by the presence of mutations in secretory proteins or by dynamic changes in the cellular microenvironment, events which are often encountered in cancers. In the ER, these events are sensed by specific sensors, which in turn trigger select signaling pathways, collectively named the unfolded-protein response (UPR) (1). The UPR is an adaptive response that allows the cells to either overcome the stress or promote cell death in the case of overwhelming burden (1). Three ER-resident proteins, namely, the protein kinase PKR-like ER kinase (PERK), the inositol-requiring protein 1 alpha (IRE1␣), and the activating transcription factor 6 alpha (ATF6␣), have been identified as the major transducers of the UPR in mammals. They display an ER luminal domain that senses misfolded proteins and are activated by a common mechanism involving the dissociation of the ER chaperone BiP/GRP78. PERK is responsible for translational attenuation through the phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2␣) (2). IRE1␣ mediates the unconventional splicing of X-box binding protein 1 (Xbp1) mRNA (3) as well as mRNA expression levels through regulated IRE1␣-dependent mRNA decay (RIDD) (4) and controls the activation of the c-jun N-terminal kinase (JNK) pathway. The third arm of the UPR is controlled by ATF6␣. This membrane-anchored transcription factor is a type II transmembrane protein regulated by intramembrane proteolysis by the Golgi apparatuslocalized site 1 and site 2 proteases (S1P and S2P) upon ER stress (5). Indeed, upon ER stress, BiP dissociates from the luminal domain of ATF6␣, thereby unmaski...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress-Activated Transcription Factor ATF6α Requires the Disulfide Isomerase PDIA5 To Modulate Chemoresistance

Higa

Taouji

Lhomond

et al. 2014

Molecular and Cellular Biology

179

156

View full text Add to dashboard Cite

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“…P-values from RankProd were used to generate a combined p-value from 14 treatments for each probeset. Combined p-values were generated using Fisher’s method (Fisher, 1932; Burguillo et al, 2010) in the survcomp package. FDR values were determined using the q-value package (Storey and Tibshirani, 2003) with the default settings.…”

Section: Methodsmentioning

confidence: 99%

Cell Identity Regulators Link Development and Stress Responses in the Arabidopsis Root

et al. 2011

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SUMMARY Stress responses in plants are tightly coordinated with developmental processes, but the interaction of these pathways is poorly understood. We used genome-wide assays at high spatio-temporal resolution to understand the processes that link development and stress in the Arabidopsis root. Our meta-analysis finds little evidence for a universal stress response. However, common stress responses appear to exist with many showing cell-type specificity. Common stress responses may be mediated by cell identity regulators, as mutations in these genes resulted in altered responses to stress. Evidence for a direct role for cell identity regulators came from genome-wide binding profiling of the key regulator SCARECROW, which showed binding to regulatory regions of stress-responsive genes. Co-expression in response to stress was used to identify genes involved in specific developmental processes. These results reveal surprising linkages between stress and development at cellular resolution, and show the power of multiple genome-wide datasets to elucidate biological processes.

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“…Clinical experience with imatinib in children comes mostly from its use for chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (49). CML occurs secondary to a translocation between chromosomes 9 and 22 (Philadelphia chromosome) resulting in a fusion gene product (BCR‐ABL), similar to that in DFSP (50).…”

Section: Treatmentmentioning

confidence: 99%

“…Significant growth retardation has been reported while undergoing treatment but resolves upon discontinuation of the drug. Adverse effects on bone development remain a concern, particularly with prolonged treatment (49).…”

Section: Treatmentmentioning

confidence: 99%

Dermatofibrosarcoma Protuberans in Children: an Update on the Diagnosis and Treatment

Kornik

Muchard

Teng

2012

Pediatric Dermatology

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Dermatofibrosarcoma protuberans (DFSP) is a fibrohistiocytic tumor of low grade malignant potential. Although rare, pediatric cases pose a particular challenge in diagnosis and management. In children, the clinical appearance may be heterogeneous and a high index of suspicion is necessary to avoid delays in diagnosis which can lead to further morbidity. Histologic examination, often with the use of appropriate immunostains, is necessary for diagnosis. Advances in the understanding of the molecular genetics of DFSP have led to further diagnostic and therapeutic modalities. DFSP is thought to result from a translocation between platelet-derived growth factor beta (PDGFB, 22q13.1) and type 1 collagen (COL1A1, 17q2122) leading to a fusion protein (PDGFB) which stimulates the PDGF receptor. Detection of this translocation in tissue via PCR or fluorescence in situ hybridization (FISH) can be helpful in difficult cases. While surgery with wide local excision or Mohs micrographic surgery is the mainstay of treatment, the use of targeted therapy with imatanib mesylate shows promise in large or unresectable tumors. Knowledge of the clinical features, histology, genetics, and treatment options is important for successful management of these tumors.

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Meta-analysis of microarray data: The case of imatinib resistance in chronic myelogenous leukemia

Cited by 12 publications

References 37 publications

Endoplasmic Reticulum Stress-Activated Transcription Factor ATF6α Requires the Disulfide Isomerase PDIA5 To Modulate Chemoresistance

Endoplasmic Reticulum Stress-Activated Transcription Factor ATF6α Requires the Disulfide Isomerase PDIA5 To Modulate Chemoresistance

Cell Identity Regulators Link Development and Stress Responses in the Arabidopsis Root

Dermatofibrosarcoma Protuberans in Children: an Update on the Diagnosis and Treatment

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