| 1. |
- Mattick, J. S., et al.
(författare)
-
Long non-coding RNAs: definitions, functions, challenges and recommendations
- 2023
-
Ingår i: Nature Reviews Molecular Cell Biology. - : Springer Science and Business Media LLC. - 1471-0072 .- 1471-0080. ; 24:6, s. 430-447
-
Tidskriftsartikel (refereegranskat)abstract
- Genes specifying long non-coding RNAs (lncRNAs) occupy a large fraction of the genomes of complex organisms. The term 'lncRNAs' encompasses RNA polymerase I (Pol I), Pol II and Pol III transcribed RNAs, and RNAs from processed introns. The various functions of lncRNAs and their many isoforms and interleaved relationships with other genes make lncRNA classification and annotation difficult. Most lncRNAs evolve more rapidly than protein-coding sequences, are cell type specific and regulate many aspects of cell differentiation and development and other physiological processes. Many lncRNAs associate with chromatin-modifying complexes, are transcribed from enhancers and nucleate phase separation of nuclear condensates and domains, indicating an intimate link between lncRNA expression and the spatial control of gene expression during development. lncRNAs also have important roles in the cytoplasm and beyond, including in the regulation of translation, metabolism and signalling. lncRNAs often have a modular structure and are rich in repeats, which are increasingly being shown to be relevant to their function. In this Consensus Statement, we address the definition and nomenclature of lncRNAs and their conservation, expression, phenotypic visibility, structure and functions. We also discuss research challenges and provide recommendations to advance the understanding of the roles of lncRNAs in development, cell biology and disease.
|
|
| 2. |
|
|
| 3. |
- Zhou, A. X., et al.
(författare)
-
The long noncoding RNA TUNAR modulates Wnt signaling and regulates human β-cell proliferation
- 2021
-
Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 320:4
-
Tidskriftsartikel (refereegranskat)abstract
- Many long noncoding RNAs (lncRNAs) are enriched in pancreatic islets and several lncRNAs are linked to type 2 diabetes (T2D). Although they have emerged as potential players in β-cell biology and T2D, little is known about their functions and mechanisms in human β-cells. We identified an islet-enriched lncRNA, TUNAR (TCL1 upstream neural differentiation-associated RNA), which was upregulated in β-cells of patients with T2D and promoted human β-cell proliferation via fine-tuning of the Wnt pathway. TUNAR was upregulated following Wnt agonism by a glycogen synthase kinase-3 (GSK3) inhibitor in human β-cells. Reciprocally, TUNAR repressed a Wnt antagonist Dickkopf-related protein 3 (DKK3) and stimulated Wnt pathway signaling. DKK3 was aberrantly expressed in β-cells of patients with T2D and displayed a synchronized regulatory pattern with TUNAR at the single cell level. Mechanistically, DKK3 expression was suppressed by the repressive histone modifier enhancer of zeste homolog 2 (EZH2). TUNAR interacted with EZH2 in β-cells and facilitated EZH2-mediated suppression of DKK3. These findings reveal a novel cell-specific epigenetic mechanism via islet-enriched lncRNA that fine-tunes the Wnt pathway and subsequently human β-cell proliferation.NEW & NOTEWORTHY The discovery that long noncoding RNA TUNAR regulates β-cell proliferation may be important in designing new treatments for diabetes.
|
|
| 4. |
- Haghbayan, M. -H, et al.
(författare)
-
MapPro : Proactive runtime mapping for dynamic workloads by quantifying ripple effect of applications on networks-on-chip
- 2015
-
Ingår i: Proceedings - 2015 9th IEEE/ACM International Symposium on Networks-on-Chip, NOCS 2015. - New York, NY, USA : Association for Computing Machinery (ACM). - 9781450333962
-
Konferensbidrag (refereegranskat)abstract
- Increasing dynamic workloads running on NoC-based many-core systems necessitates efficient runtime mapping strategies. With an unpredictable nature of application profiles, selecting a rational region to map an incoming application is an NP-hard problem in view of minimizing congestion and maximizing performance. In this paper, we propose a proactive region selection strategy which prioritizes nodes that offer lower congestion and dispersion. Our proposed strategy, MapPro, quantitatively represents the propagated impact of spatial availability and dispersion on the network with every new mapped application. This allows us to identify a suitable region to accommodate an incoming application that results in minimal congestion and dispersion. We cluster the network into squares of different radii to suit applications of different sizes and proactively select a suitable square for a new application, eliminating the overhead caused with typical reactive mapping approaches. We evaluated our proposed strategy over different traffic patterns and observed gains of up to 41% in energy efficiency, 28% in congestion and 21% dispersion when compared to the state-of-the-art region selection methods. Copyright 2015 ACM.
|
|
| 5. |
|
|
| 6. |
- Kanduri, A., et al.
(författare)
-
Dark silicon patterning : Efficient power utilization through run-time mapping
- 2017
-
Ingår i: The Dark Side of Silicon. - Cham : Springer. - 9783319315966 - 9783319315942 ; , s. 237-258
-
Bokkapitel (refereegranskat)abstract
- An efficient run-time application mapping approach can considerably enhance resource utilization and mitigate the dark silicon phenomenon. In this chapter, we present a dark silicon aware run-time application mapping approach that patterns active cores alongside the inactive cores in order to evenly distribute power density across the chip. This approach leverages dark silicon to balance the temperature of active cores to provide higher power budget and better resource utilization, within a safe peak operating temperature. In contrast to exhaustive search based mapping techniques, the proposed agile heuristic approach has a negligible run-time overhead. This patterning strategy yields a surplus power budget of up to 17?% along with an improved throughput of up to 21?% in comparison with other state-of-the-art run-time mapping strategies, while the surplus budget is as high as 40?% compared to worst case scenarios.
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Mondal, Tanmoy, 1981, et al.
(författare)
-
MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA–DNA triplex structures
- 2015
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Long noncoding RNAs (lncRNAs) regulate gene expression by association with chromatin, but how they target chromatin remains poorly understood. We have used chromatin RNA immunoprecipitation-coupled high-throughput sequencing to identify 276 lncRNAs enriched in repressive chromatin from breast cancer cells. Using one of the chromatin-interacting lncRNAs, MEG3, we explore the mechanisms by which lncRNAs target chromatin. Here we show that MEG3 and EZH2 share common target genes, including the TGF-β pathway genes. Genome-wide mapping of MEG3 binding sites reveals that MEG3 modulates the activity of TGF-β genes by binding to distal regulatory elements. MEG3 binding sites have GA-rich sequences, which guide MEG3 to the chromatin through RNA–DNA triplex formation. We have found that RNA–DNA triplex structures are widespread and are present over the MEG3 binding sites associated with the TGF-β pathway genes. Our findings suggest that RNA–DNA triplex formation could be a general characteristic of target gene recognition by the chromatin-interacting lncRNAs.
|
|
| 10. |
|
|
| 11. |
- Wiel, Clotilde, 1987, et al.
(författare)
-
BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis
- 2019
-
Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 178:2, s. 330-345
-
Tidskriftsartikel (refereegranskat)abstract
- For tumors to progress efficiently, cancer cells must overcome barriers of oxidative stress. Although dietary antioxidant supplementation or activation of endogenous antioxidants by NRF2 reduces oxidative stress and promotes early lung tumor progression, little is known about its effect on lung cancer metastasis. Here, we show that long-term supplementation with the antioxidants N-acetylcysteine and vitamin E promotes KRAS-driven lung cancer metastasis. The antioxidants stimulate metastasis by reducing levels of free heme and stabilizing the transcription factor BACH1. BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells. Targeting BACH1 normalized glycolysis and prevented antioxidant-induced metastasis, while increasing endogenous BACH1 expression stimulated glycolysis and promoted metastasis, also in the absence of antioxidants. We conclude that BACH1 stimulates glycolysis-dependent lung cancer metastasis and that BACH1 is activated under conditions of reduced oxidative stress.
|
|
| 12. |
|
|
| 13. |
- Athie, Alejandro, et al.
(författare)
-
Analysis of copy number alterations reveals the lncRNA ALAL-1 as a regulator of lung cancer immune evasion
- 2020
-
Ingår i: The Journal of cell biology. - : Rockefeller University Press. - 1540-8140 .- 0021-9525. ; 219:9
-
Tidskriftsartikel (refereegranskat)abstract
- Cancer is characterized by genomic instability leading to deletion or amplification of oncogenes or tumor suppressors. However, most of the altered regions are devoid of known cancer drivers. Here, we identify lncRNAs frequently lost or amplified in cancer. Among them, we found amplified lncRNA associated with lung cancer-1 (ALAL-1) as frequently amplified in lung adenocarcinomas. ALAL-1 is also overexpressed in additional tumor types, such as lung squamous carcinoma. The RNA product of ALAL-1 is able to promote the proliferation and tumorigenicity of lung cancer cells. ALAL-1 is a TNFα- and NF-κB-induced cytoplasmic lncRNA that specifically interacts with SART3, regulating the subcellular localization of the protein deubiquitinase USP4 and, in turn, its function in the cell. Interestingly, ALAL-1 expression inversely correlates with the immune infiltration of lung squamous tumors, while tumors with ALAL-1 amplification show lower infiltration of several types of immune cells. We have thus unveiled a pro-oncogenic lncRNA that mediates cancer immune evasion, pointing to a new target for immune potentiation.
|
|
| 14. |
|
|
| 15. |
- Kanduri, A., et al.
(författare)
-
A perspective on dark silicon
- 2017
-
Ingår i: The Dark Side of Silicon. - Cham : Springer. - 9783319315966 - 9783319315942 ; , s. 3-20
-
Bokkapitel (refereegranskat)abstract
- The possibilities to increase single-core performance have ended due to limited instruction-level parallelism and a high penalty when increasing frequency. This prompted designers to move toward multi-core paradigms [1], largely supported by transistor scaling [2]. Scaling down transistor gate length makes it possible to switch them faster at a lower power, as they have a low capacitance. In this context, an important consideration is power density-the power dissipated per unit area. Dennard’s scaling establishes that reducing physical parameters of transistors allows operating them at lower voltage and thus at lower power, because power consumption is proportional to the square of the applied voltage, keeping power density constant [3]. Dennard’s estimation of scaling effects and constant power density is shown in Table 1.1. Theoretically, scaling down further should result in more computational capacity per unit area. However, scaling is reaching its physical limits to an extent that voltage cannot be scaled down as much as transistor gate length leading to failure of Dennardian trend. This along with a rise in leakage current results in increased power density, rather than a constant power density. Higher power density implies more heat generated in a unit area and hence higher chip temperatures which have to be dissipated through cooling solutions, as increase in temperature beyond a certain level results in unreliable functionality, faster aging, and even permanent failure of the chip. To ensure a safe operation, it is essential for the chip to perform within a fixed power budget [4]. In order to avoid too high power dissipation, a certain part of the chip needs to remain inactive; the inactive part is termed dark silicon [5]. Hence, we have to operate working cores in a multi-core system at less than their full capacity, limiting the performance, resource utilization, and efficiency of the system.
|
|
| 16. |
- Kanduri, Anil, et al.
(författare)
-
Accuracy-Aware Power Management for Many-Core Systems Running Error-Resilient Applications
- 2017
-
Ingår i: IEEE Transactions on Very Large Scale Integration (vlsi) Systems. - : IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC. - 1063-8210 .- 1557-9999. ; 25:10, s. 2749-2762
-
Tidskriftsartikel (refereegranskat)abstract
- Power capping techniques based on dynamic voltage and frequency scaling (DVFS) and power gating (PG) are oriented toward power actuation, compromising on performance and energy. Inherent error resilience of emerging application domains, such as Internet-of-Things (IoT) and machine learning, provides opportunities for energy and performance gains. Leveraging accuracy-performance tradeoffs in such applications, we propose approximation (APPX) as another knob for close-looped power management, to complement power knobs with performance and energy gains. We design a power management framework, APPEND+, that can switch between accurate and approximate modes of execution subject to system throughput requirements. APPEND+ considers the sensitivity of the application to error to make disciplined alteration between levels of APPX such that performance is maximized while error is minimized. We implement a power management scheme that uses APPX, DVFS, and PG knobs hierarchically. We evaluated our proposed approach over machine learning and signal processing applications along with two case studies on IoT-early warning score system and fall detection. APPEND+ yields 1.9x higher throughput, improved latency up to five times, better performance per energy, and dark silicon mitigation compared with the state-of-the-art power management techniques over a set of applications ranging from high to no error resilience.
|
|
| 17. |
- Kanduri, Anil, et al.
(författare)
-
Approximation Knob : Power Capping Meets Energy Efficiency
- 2016
-
Ingår i: 2016 IEEE/ACM INTERNATIONAL CONFERENCE ON COMPUTER-AIDED DESIGN (ICCAD). - New York, NY, USA : Institute of Electrical and Electronics Engineers (IEEE). - 9781450344661
-
Konferensbidrag (refereegranskat)abstract
- Power Capping techniques are used to restrict power consumption of computer systems to a thermally safe limit. Current many-core systems employ dynamic voltage and frequency scaling (DVFS), power gating (PG) and scheduling methods as actuators for power capping. These knobs are oriented towards power actuation, while the need for performance and energy savings are increasing in the dark silicon era. To address this, we propose approximation (APPX) as another knob for close-looped power management, lending performance and energy efficiency to existing power capping techniques. We use approximation in a pro-active way for long-term performance-energy objectives, complementing the short-term reactive power objectives. We implement an approximation-enabled power management framework, APPEND, that dynamically chooses an application with appropriate level of approximation from a set of variable accuracy implementations. Subject to the system dynamics, our power manager chooses an effective combination of knobs APPX, DVFS and PG, in a hierarchical way to ensure power capping with performance and energy gains. Our proposed approach yields 1.5x higher throughput, improved latency upto 5x, better performance per energy and dark silicon mitigation compared to state-of-the-art power management techniques over a set of applications ranging from high to no error resilience.
|
|
| 18. |
- Kanduri, Meena, 1974, et al.
(författare)
-
Distinct transcriptional control in major immunogenetic subsets of chronic lymphocytic leukemia exhibiting subset-biased global DNA methylation profiles.
- 2012
-
Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 7:12, s. 1435-42
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic lymphocytic leukemia (CLL) can be divided into prognostic subgroups based on the IGHV gene mutational status, and is further characterized by multiple subsets of cases with quasi-identical or stereotyped B cell receptors that also share clinical and biological features. We recently reported differential DNA methylation profiles in IGHV-mutated and IGHV-unmutated CLL subgroups. For the first time, we here explore the global methylation profiles of stereotyped subsets with different prognosis, by applying high-resolution methylation arrays on CLL samples from three major stereotyped subsets: the poor-prognostic subsets #1 (n = 15) and #2 (n = 9) and the favorable-prognostic subset #4 (n = 15). Overall, the three subsets exhibited significantly different methylation profiles, which only partially overlapped with those observed in our previous study according to IGHV gene mutational status. Specifically, gene ontology analysis of the differentially methylated genes revealed a clear enrichment of genes involved in immune response, such as B cell activation (e.g., CD80, CD86 and IL10), with higher methylation levels in subset #1 than subsets #2 and #4. Accordingly, higher expression of the co-stimulatory molecules CD80 and CD86 was demonstrated in subset #4 vs. subset #1, pointing to a key role for these molecules in the crosstalk of CLL subset #4 cells with the microenvironment. In summary, investigation of three prototypic, stereotyped CLL subsets revealed distinct DNA methylation profiles for each subset, which suggests subset-biased patterns of transcriptional control and highlights a key role for epigenetics during leukemogenesis.
|
|
| 19. |
- Kopparapu, Pradeep Kumar, et al.
(författare)
-
Epigenetic silencing of miR-26A1 in chronic lymphocytic leukemia and mantle cell lymphoma : Impact on EZH2 expression
- 2016
-
Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 11:5, s. 335-343
-
Tidskriftsartikel (refereegranskat)abstract
- Downregulation of miR26A1 has been reported in various B-cell malignancies; however, the mechanism behind its deregulation remains largely unknown. We investigated miR26A1 methylation and expression levels in a well-characterized series of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). From 450K methylation arrays, we first observed miR26A1 (cg26054057) as uniformly hypermethylated in MCL (n = 24) (all >75%), while CLL (n = 18) showed differential methylation between prognostic subgroups. Extended analysis using pyrosequencing confirmed our findings and real-time quantitative PCR verified low miR26A1 expression in both CLL (n = 70) and MCL (n = 38) compared to normal B-cells. Notably, the level of miR26A1 methylation predicted outcome in CLL, with higher levels seen in poor-prognostic, IGHV-unmutated CLL. Since EZH2 was recently reported as a target for miR26A1, we analyzed the expression levels of both miR26A1 and EZH2 in primary CLL samples and observed an inverse correlation. By overexpression of miR26A1 in CLL and MCL cell lines, reduced EZH2 protein levels were observed using both Western blot and flow cytometry. In contrast, methyl-inhibitor treatment led to upregulated miR26A1 expression with a parallel decrease of EZH2 expression. Finally, increased levels of apoptosis were observed in miR26A1-overexpressing cell lines, further underscoring the functional relevance of miR26A1. In summary, we propose that epigenetic silencing of miR26A1 is required for the maintenance of increased levels of EZH2, which in turn translate into a worse outcome, as shown in CLL, highlighting miR26A1 as a tumor suppressor miRNA.
|
|
| 20. |
- Kopparapu, Pradeep Kumar, et al.
(författare)
-
Epigenetic silencing of miR-26A1 in chronic lymphocytic leukemia and mantle cell lymphoma: Impact on EZH2 expression. : Epigenetic inactivation of miR - 26A1 in CLL and MCL
- 2016
-
Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 11:5, s. 335-343
-
Tidskriftsartikel (refereegranskat)abstract
- Downregulation of miR26A1 has been reported in various B-cell malignancies; however, the mechanism behind its deregulation remains largely unknown. We investigated miR26A1 methylation and expression levels in a well-characterized series of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). From 450K methylation arrays, we first observed miR26A1 (cg26054057) as uniformly hypermethylated in MCL (n=24) (all >75%), while CLL (n=18) showed differential methylation between prognostic subgroups. Extended analysis using pyrosequencing confirmed our findings and real-time quantitative PCR verified low miR26A1 expression in both CLL (n=70) and MCL (n=38) compared to normal B-cells. Notably, the level of miR26A1 methylation predicted outcome in CLL, with higher levels seen in poor-prognostic, IGHV-unmutated CLL. Since EZH2 was recently reported as a target for miR26A1, we analyzed the expression levels of both miR26A1 and EZH2 in primary CLL samples and observed an inverse correlation. By overexpression of miR26A1 in CLL and MCL cell lines, reduced EZH2 protein levels were observed using both Western blot and flow cytometry. In contrast, methyl-inhibitor treatment led to upregulated miR26A1 expression with a parallel decrease of EZH2 expression. Finally, increased levels of apoptosis were observed in miR26A1-overexpressing cell lines, further underscoring the functional relevance of miR26A1. In summary, we propose that epigenetic silencing of miR26A1 is required for the maintenance of increased levels of EZH2, which in turn translate into a worse outcome, as shown in CLL, highlighting miR26A1 as a tumor suppressor miRNA.
|
|
| 21. |
|
|
| 22. |
- Liang, L, et al.
(författare)
-
Dynamic readjustment of parental methylation patterns of the 5'-flank ofthe mouse H19 gene during in vitro organogenesis
- 2000
-
Ingår i: International Journal of Developmental Biology. - 0214-6282 .- 1696-3547. ; 44, s. 785-790
-
Tidskriftsartikel (refereegranskat)abstract
- Gametic marks are stably propagated in order to manifest parent of origin-specific expression patterns of imprinted genes in the developing conceptus. Although the character of the imprint has not yet been fully elucidated, there is compelling evidence that it involves a methylation mark. This is exemplified by a region upstream of the H19 gene, which is not only methylated in a parent of origin-specific manner, but also regulates the silencing of the maternal Igf2 and paternal H19 alleles, respectively. We show here that the parental-specific methylation patterns within the differentially methylated domain (DMD) are perturbed in the soma during in vitro organogenesis. Under these conditions, the paternal DMD allele becomes partially demethylated, whereas the maternal DMD allele gains methylation. Despite these effects, there were no changes in allelic Igf2 or H19 expression patterns in the embryo. Finally, we show that although TSA derepresses the paternal H19 allele in ectoplacental cone when in vitro developed, there is no discernible effect on the methylation status of the paternally inherited 5'-flank in comparison to control samples. Collectively, this data demonstrates that the parental mark is sensitive to a subset of environmental cues and that a certain degree of plasticity of the gametic mark is tolerated without affecting the manifestation of the imprinted state.
|
|
| 23. |
- Ma, Haixia, et al.
(författare)
-
The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes
- 2023
-
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 299:6
-
Tidskriftsartikel (refereegranskat)abstract
- In recent years, lactate has been recognized as an important circulating energy substrate rather than only a dead-end metabolic waste product generated during glucose oxidation at low levels of oxygen. The term "aerobic glycolysis" has been coined to denote increased glucose uptake and lactate pro-duction despite normal oxygen levels and functional mito-chondria. Hence, in "aerobic glycolysis," lactate production is a metabolic choice, whereas in "anaerobic glycolysis," it is a metabolic necessity based on inadequate levels of oxygen. Interestingly, lactate can be taken up by cells and oxidized to pyruvate and thus constitutes a source of pyruvate that is in-dependent of insulin. Here, we show that the transcription factor Foxp1 regulates glucose uptake and lactate production in adipocytes and myocytes. Overexpression of Foxp1 leads to increased glucose uptake and lactate production. In addition, protein levels of several enzymes in the glycolytic pathway are upregulated, such as hexokinase 2, phosphofructokinase, aldolase, and lactate dehydrogenase. Using chromatin immu-noprecipitation and real-time quantitative PCR assays, we demonstrate that Foxp1 directly interacts with promoter consensus cis-elements that regulate expression of several of these target genes. Conversely, knockdown of Foxp1 suppresses these enzyme levels and lowers glucose uptake and lactate production. Moreover, mice with a targeted deletion of Foxp1 in muscle display systemic glucose intolerance with decreased muscle glucose uptake. In primary human adipocytes with induced expression of Foxp1, we find increased glycolysis and glycolytic capacity. Our results indicate Foxp1 may play an important role as a regulator of aerobic glycolysis in adipose tissue and muscle.
|
|
| 24. |
|
|
| 25. |
- Mitra, Sanhita, et al.
(författare)
-
Subcellular distribution of p53 by the p53-responsive lncRNA NBAT1 determines chemotherapeutic response in neuroblastoma.
- 2021
-
Ingår i: Cancer research. - 1538-7445. ; 81:6, s. 1457-1471
-
Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma has a low mutation rate for the p53 gene. Alternative ways of p53 inactivation have been proposed in neuroblastoma, such as abnormal cytoplasmic accumulation of wild-type p53. However, mechanisms leading to p53 inactivation via cytoplasmic accumulation are not well investigated. Here we show that the neuroblastoma risk-associated locus 6p22.3-derived tumor suppressor NBAT1 is a p53-responsive lncRNA that regulates p53 subcellular levels. Low expression of NBAT1 provided resistance to genotoxic drugs by promoting p53 accumulation in cytoplasm and loss from mitochondrial and nuclear compartments. Depletion of NBAT1 altered CRM1 function and contributed to the loss of p53-dependent nuclear gene expression during genotoxic drug treatment. CRM1 inhibition rescued p53-dependent nuclear functions and sensitized NBAT1-depleted cells to genotoxic drugs. Combined inhibition of CRM1 and MDM2 was even more effective in sensitizing aggressive neuroblastoma cells with p53 cytoplasmic accumulation. Thus, our mechanistic studies uncover an NBAT1-dependent CRM1/MDM2-based potential combination therapy for high-risk neuroblastoma patients.
|
|
| 26. |
|
|
