LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro

Huang, Tien-sheng; Myklebust, Line M.; Kjarland, E.; Gjertsen, Bjørn Tore; Pendino, Frédéric; Bruserud, Øystein; Døskeland, Stein Ove; Lillehaug, Johan R.

doi:10.1186/1476-4598-6-31

Cited by 59 publications

(84 citation statements)

References 34 publications

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“…LEDGF/p75 is a potent oncogene with known diverse functions in cell survival, chemotherapy resistance, tumor progression (41,48,49), and leukemic transformation via interactions with MLL oncoproteins (30). Although our studies indicated a tight convergence of LEDGF/p75 and JPO2 on promigratory AKT signaling, we observed that JPO2 and LEDGF/p75 did not always have overlapping cellular and signaling effects in UW228 and UW426 medulloblastoma cell lines.…”

Section: Discussioncontrasting

confidence: 41%

“…Future studies to determine how JPO2 and the PI3K/AKT pathway act convergently or independently to mediate EMT and migratory/metastatic medulloblastoma phenotypes would clearly be of therapeutic interest. We observed that JPO2 binds to LEDGF/p75, a known oncoprotein highly expressed in multiple cancer types (31,40,41), that is also coordinately upregulated with JPO2 in medulloblastoma. Our data, which is the first to implicate LEDGF/p75 in medulloblastoma suggest LEDGF/p75 and JPO2 may act via a common transcriptional signaling complex to promote Myc:PI3K/AKTassociated medulloblastoma transformation.…”

Section: Discussionmentioning

confidence: 86%

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JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

et al. 2016

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Substantial evidence links Myc-PI3K/AKT signaling to the most aggressive subtype of medulloblastoma and this axis in medulloblastoma therapy. In this study, we advance understanding of how Myc-PI3K/AKT signaling contributes to this malignancy, specifically, in identifying the Myc-interacting protein JPO2 and its partner binding protein LEDGF/p75 as critical modulators of PI3K/AKT signaling and metastasis in medulloblastoma. JPO2 overexpression induced metastatic medulloblastoma in vivo through two synergistic feed-forward regulatory circuits involving LEDGF/p75 and AKT that promote metastatic phenotypes in this setting. Overall, our findings highlight two novel prometastatic loci in medulloblastoma and point to the JPO2:LEDGF/p75 protein complex as a potentially new targetable component of PI3K/AKT signaling in medulloblastoma. Cancer Res; 76(9);

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Section: Discussioncontrasting

confidence: 41%

Section: Discussionmentioning

confidence: 86%

JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

et al. 2016

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“…Comprehensive gene analysis on a microarray in cervical carcinoma cells (squamous cell carcinoma) showed that MT-CO1 was increased by a factor greater than two in RRCs compared with radiosensitive cells (15). Also, in human acute myelogenic leukemia cells, MT-CO3 was upregulated in chemoresistant cells compared with in chemosensitive cells (16). However, these study did not verify that overexpression of MT-CO1 actually induces radioresistance.…”

Section: Discussioncontrasting

confidence: 42%

“…The relationship between cytochrome c oxidase and chemo or radioresistance has been reported in various tumor cell lines (15)(16)(17)(18)(19). Comprehensive gene analysis on a microarray in cervical carcinoma cells (squamous cell carcinoma) showed that MT-CO1 was increased by a factor greater than two in RRCs compared with radiosensitive cells (15).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of cytochrome c oxidase 1 induced radioresistance in esophageal squamous cell carcinoma

et al. 2017

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Abstract. Comprehensive gene screening with transposons is a novel procedure for the systematic identification of resistant genes. The present study aimed to use this technique to identify candidate radioresistant genes in esophageal squamous cell carcinoma. A transposon is a base sequence that can translocate to another location in the genome at random. By inserting the cytomegalovirus promotor as a transcriptional activator in the transposon, the following gene in the new location becomes overexpressed and the gene located at the transposon insertion site is downregulated. Consequently, various transposon-tagged cells, which have differentially overexpressed or downregulated genes using the transposon method can be obtained. Following the irradiation of transposon-tagged cells, candidate radioresistant genes can be selected in order to detect the location of the transposon in the cells that have survived. A total of 11 genes were detected as candidate radioresistant genes. Cytochrome c oxidase 1 (MT-CO1), an enzyme involved in apoptosis through the activation of the caspase cascade, was one of the candidate genes identified. The relative expression level of MT-CO1 was 0.12 in MT-CO1-downregulated cells which was significantly lower compared with the expression level in parent TE4 cells (P<0.001). The survival rate was 28.7% in MT-CO1-downregulated cells and 10.5% in parent TE4 cells 9 days following 5-Gy irradiation. The activity of cytochrome c and caspase-3 following irradiation was significantly lower in the MT-CO1-downregulated radioresistant cells compared with in TE4 cells. In conclusion, the novel gene screening technique demonstrated to be useful for detecting candidate radioresistant genes in esophageal squamous cell carcinoma. The results of the present study revealed that the downregulation of MT-CO1 induced radioresistance occurs by inhibiting the activation of the caspase cascade in radioresistant esophageal cancer cells.

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“…In −/− mouse embryonic fibroblasts (MEFs) fewer genes were up-or down-regulated (< 200) and, again, a particular transcriptional network was not identified [101]. Studies focused on other biological questions have implicated p75 in modulating apoptosis and other cellular responses to stress and have suggested a role as an auto-antigen in certain disease states [66][67][68][70][71][72]84,107]. However, p75 depletion does not disproportionately alter stress-responsive gene transcription, nor does HIV appear to preferentially target such genes [85,101,110].…”

Section: P75: Identification and Putative Cellular Function Of A Lentmentioning

confidence: 99%

Integrase, LEDGF/p75 and HIV replication

Poeschla

2008

Cell. Mol. Life Sci.

115

104

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HIV integrates a DNA copy of its genome into a host cell chromosome in each replication cycle. The essential DNA cleaving and joining chemistry of integration is known, but there is less understanding of the process as it occurs in a cell, where two complex and dynamic macromolecular entities are joined: the viral pre-integration complex and chromatin. Among implicated cellular factors, much recent attention has coalesced around LEDGF/p75, a nuclear protein that may act as a chromatin docking factor or receptor for lentiviral pre-integration complexes. LEDGF/p75 tethers HIV integrase to chromatin, protects it from degradation, and strongly influences the genome-wide pattern of HIV integration. Depleting the protein from cells and/or over-expressing its integrase-binding domain blocks viral replication. Current goals are to establish the underlying mechanisms and to determine whether this knowledge can be exploited for antiviral therapy or for targeting lentiviral vector integration in human gene therapy.

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LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro

Cited by 59 publications

References 34 publications

JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

Downregulation of cytochrome c oxidase 1 induced radioresistance in esophageal squamous cell carcinoma

Integrase, LEDGF/p75 and HIV replication

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