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  • 1
    Online Resource
    Online Resource
    Arsenic Sulfide Binds c-CBL to Promote BCR-ABL Ubiquitination and Degradation In Chronic Myelogenous Leukemia.
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 1200-1200
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1200-1200
    Abstract: Abstract 1200 Using immunoprecipitation (IP)-2D-nano-HPLC-MALDI-MS-MS, we identified c-CBL in association with BCR-ABL in a multi-protein complex in K562 cells. In vitro ubiquitination and mutagenesis analyses show that c-CBL serves as a specific E3 ligase for ubiquitination of BCR-ABL at K1517. Arsenic sulfide (As4S4) treatment results in increased c-CBL protein level, which promotes ubiquitination and subsequent degradation of BCR-ABL and apoptosis of K562 cells. Elevated c-CBL is necessary and sufficient to recapitulate the effect of As4S4. Interestingly, arsenic directly binds the RING finger domain of c-CBL, inhibiting its self-ubiquitination and degradation, thus leading to accumulation of c-CBL. However, this interaction between As4S4 and c-CBL does not interfere with its E3 ligase activity towards BCR-ABL. Increased c-CBL protein and BCR-ABL degradation are also observed in vivo after As4S4 administration in BCR-ABL leukemia mice. These findings provide insights into the molecular mechanisms of arsenic and its potential therapeutic applications in CML. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.1200.1200
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 2
    Online Resource
    Online Resource
    Systems Understanding of Synergism Between As4S4 and Imatinib in Treating BCR/ABL Leukemia Model and in Attenuating BCR/ABL Oncoprotein as Well as Related Regulatory Networks
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 4234-4234
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 4234-4234
    Abstract: The combination of Imatinib and arsenic sulfide (As4S4) exerts more profound in vivo therapeutic effects on chronic myeloid leukemia (CML) at both organism and cellular levels, as evident for the first time in this paper by significantly prolonged lifespan in mouse leukemia model bearing BCR/ABL and induction of apoptosis of BCR/ABL expressing cells. To address mechanisms underlying this synergy, we performed systematic analysis of the dynamic change of proteome, phosphoproteome and transcriptome in K562 cells after As4S4 and/or Imatinib treatment with the support of principal component analysis (PCA) and self-organization maps (SOM). Moreover, protein biochemistry experiments were performed to confirm the important conclusions from multiomics study. The integrated information indicated that As4S4 promoted the unfolding protein reaction (UPR) and activity of ubiquitination pathway, which can be considered as a major biochemical basis of the pharmacological effects of this ancient medicine. In this context, As4S4 was shown to target BCR/ABL through ubiquitination of key lysine residues and led subsequently to its degradation by proteasome. Meanwhile, Imatinib inhibited the PI3K/AKT/mTOR pathway with synergism of As4S4 and arrested cell cycle. Combination of the two agents synergistically decreased activity and quantity of BCR/ABL and activated intrinsic and extrinsic apoptosis pathways. These complex multi-molecular target and multi-pathway modifications at protein level, together with those at transcriptional regulation level, ultimately resulted in the synergistic attenuation of BCR/ABL oncoprotein and the therapeutic effects on CML model.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.4234.4234
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia
    American Society of Hematology ; 2011
    In:  Blood Vol. 117, No. 24 ( 2011-06-16), p. 6425-6437
    Details
    In: Blood, American Society of Hematology, Vol. 117, No. 24 ( 2011-06-16), p. 6425-6437
    Abstract: Arsenic had been used in treating malignancies from the 18th to mid-20th century. In the past 3 decades, arsenic was revived and shown to be able to induce complete remission and to achieve, when combined with all-trans retinoic acid and chemotherapy, a 5-year overall survival of 90% in patients with acute promyelocytic leukemia driven by the t(15;17) translocation-generated promyelocytic leukemia–retinoic acid receptor α (PML-RARα) fusion. Molecularly, arsenic binds thiol residues and induces the formation of reactive oxygen species, thus affecting numerous signaling pathways. Interestingly, arsenic directly binds the C3HC4 zinc finger motif in the RBCC domain of PML and PML-RARα, induces their homodimerization and multimerization, and enhances their interaction with the SUMO E2 conjugase Ubc9, facilitating subsequent sumoylation/ubiquitination and proteasomal degradation. Arsenic-caused intermolecular disulfide formation in PML also contributes to PML-multimerization. All-trans retinoic acid, which targets PML-RARα for degradation through its RARα moiety, synergizes with arsenic in eliminating leukemia-initiating cells. Arsenic perturbs a number of proteins involved in other hematologic malignancies, including chronic myeloid leukemia and adult T-cell leukemia/lymphoma, whereby it may bring new therapeutic benefits. The successful revival of arsenic in acute promyelocytic leukemia, together with modern mechanistic studies, has thus allowed a new paradigm to emerge in translational medicine.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2010-11-283598
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice
    Springer Science and Business Media LLC ; 2006
    In:  Nature Genetics Vol. 38, No. 8 ( 2006-8), p. 926-930
    Details
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 38, No. 8 ( 2006-8), p. 926-930
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    URL: Article
    DOI: 10.1038/ng1836
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2006
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    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Genetic interactions between Pten and p53 in radiation-induced lymphoma development
    Springer Science and Business Media LLC ; 2003
    In:  Oncogene Vol. 22, No. 52 ( 2003-11-20), p. 8379-8385
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 22, No. 52 ( 2003-11-20), p. 8379-8385
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/sj.onc.1207083
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2003
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  • 6
    Online Resource
    Online Resource
    Murine Microenvironment Metaprofiles Associate with Human Cancer Etiology and Intrinsic Subtypes
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 6 ( 2013-03-15), p. 1353-1362
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 6 ( 2013-03-15), p. 1353-1362
    Abstract: Purpose: Ionizing radiation is a well-established carcinogen in rodent models and a risk factor associated with human cancer. We developed a mouse model that captures radiation effects on host biology by transplanting unirradiated Trp53-null mammary tissue to sham or irradiated hosts. Gene expression profiles of tumors that arose in irradiated mice are distinct from those that arose in naïve hosts. We asked whether expression metaprofiles could discern radiation-preceded human cancer or be informative in sporadic breast cancers. Experimental Design: Affymetrix microarray gene expression data from 56 Trp53-null mammary tumors were used to define gene profiles and a centroid that discriminates tumors arising in irradiated hosts. These were applied to publicly available human cancer datasets. Results: Host irradiation induces a metaprofile consisting of gene modules representing stem cells, cell motility, macrophages, and autophagy. Human orthologs of the host irradiation metaprofile discriminated between radiation-preceded and sporadic human thyroid cancers. An irradiated host centroid was strongly associated with estrogen receptor–negative breast cancer. When applied to sporadic human breast cancers, the irradiated host metaprofile strongly associated with basal-like and claudin-low breast cancer intrinsic subtypes. Comparing host irradiation in the context of TGF-β levels showed that inflammation was robustly associated with claudin-low tumors. Conclusions: Detection of radiation-preceded human cancer by the irradiated host metaprofile raises possibilities of assessing human cancer etiology. Moreover, the association of the irradiated host metaprofiles with estrogen receptor–negative status and claudin-low subtype suggests that host processes similar to those induced by radiation underlie sporadic cancers. Clin Cancer Res; 19(6); 1353–62. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-12-3554
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 7
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    CUL4A Induces Epithelial–Mesenchymal Transition and Promotes Cancer Metastasis by Regulating ZEB1 Expression
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 2 ( 2014-01-15), p. 520-531
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 2 ( 2014-01-15), p. 520-531
    Abstract: The ubiquitin ligase CUL4A has been implicated in tumorigenesis, but its contributions to progression and metastasis have not been evaluated. Here, we show that CUL4A is elevated in breast cancer as well as in ovarian, gastric, and colorectal tumors in which its expression level correlates positively with distant metastasis. CUL4A overexpression in normal or malignant human mammary epithelial cells increased their neoplastic properties in vitro and in vivo, markedly increasing epithelial–mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing CUL4A in aggressive breast cancer cells inhibited these processes. Mechanistically, we found that CUL4A modulated histone H3K4me3 at the promoter of the EMT regulatory gene ZEB1 in a manner associated with its transcription. ZEB1 silencing blocked CUL4A-driven proliferation, EMT, tumorigenesis, and metastasis. Furthermore, in human breast cancers, ZEB1 expression correlated positively with CUL4A expression and distant metastasis. Taken together, our findings reveal a pivotal role of CUL4A in regulating the metastatic behavior of breast cancer cells. Cancer Res; 74(2); 520–31. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-13-2182
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 8
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    Online Resource
    Abstract 3326: Low dose radiation alters stromal epithelial interactions to enrich for estrogen receptor(ER)α-negative stem cells and subsequent ER-negative tumors
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3326-3326
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3326-3326
    Abstract: What determines the prevalence of ERα in breast cancer is not well-understood. ER-negative breast cancer is most frequent in young women and certain racial groups, particularly African-American women. We have used a model in which p53 null mammary epithelium is orthotopically transplanted to an irradiated mouse to study radiation effects on host interactions during the development of breast cancer. We observed that host irradiation increased the rate of tumor development, which were significantly more likely to be ERα-negative and PR-negative tumors. These data implicate radiation-induced heterotypic signaling in determining critical clinical features of breast cancer. We then asked how different the expression profiles of ER-negative tumors were in sham and irradiated hosts as a means to infer whether they develop via similar paths. SAM-tandem-bootstrap identified 115 genes that cluster ER-negative tumors from irradiated versus sham-irradiated hosts, but not ER-positive tumors. Mouse Trp53 null tumors are similar to claudin-low breast cancer and both are enriched in the mammary stem cell (MaSC) signature reported by Visvader and colleagues. Since the mammary stem cell is ER-negative, as are tumors that are enriched in the MaSC signature, we asked how the MaSC profile related to the ER-115 profile that clusters tumors from irradiated hosts. Genes up-regulated in the ER-115 signature showed a highly significant (p=0.01) enrichment for genes up-regulated in the MaSC profile using ConceptGen. We also found that MaSC genes were significantly enriched in irradiated mammary glands. Together these data suggested the hypothesis that low dose radiation might affect the mammary lineage hierarchy by altering self-renewal in mammary stem cells. To test this idea, mice were irradiated with 10 or 100 cGy at 3 weeks of age and mammary cells isolated from fully mature 12 week old mice were analyzed by FACS using Cd24med/Cd49hi mammary repopulation markers. The proportion of lin-/ Cd24med/Cd49hi cells in irradiated mice was significantly increased (p & lt;0.05) compared to sham-irradiated mice. Functional analysis of repopulating potential is the gold standard to assess the number of stem cells in rodent mammary gland. Thus we isolated mammary cells from 8 week old mice that were sham-irradiated or irradiated with 10 cGy at 3 weeks. Mammary repopulating activity was increased ∼1.7 fold (p & lt;0.05) in irradiated mice compared to sham-irradiated mice, again without evidence of dose dependence. Together our data suggest that low dose host irradiation increases mammary repopulating activity, which increases the propensity for neoplastic transformation and the prevalence of ER-negative tumors. Supported by DOE Low Dose Radiation Program, NIEHS Breast Cancer and the Environment Research Center, and DOD Breast Cancer Research Fellowship to DHN. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3326. doi:10.1158/1538-7445.AM2011-3326
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3326
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 9
    Online Resource
    Online Resource
    A Mouse Skin Multistage Carcinogenesis Model Reflects the Aberrant DNA Methylation Patterns of Human Tumors
    American Association for Cancer Research (AACR) ; 2004
    In:  Cancer Research Vol. 64, No. 16 ( 2004-08-15), p. 5527-5534
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 64, No. 16 ( 2004-08-15), p. 5527-5534
    Abstract: Whereas accepted models of tumorigenesis exist for genetic lesions, the timing of epigenetic alterations in cancer is not clearly understood. We have analyzed the profile of aberrations in DNA methylation occurring in cells lines and primary tumors of one of the best-characterized mouse carcinogenesis systems, the multistage skin cancer progression model. Initial analysis using high-performance capillary electrophoresis and immunolocalization revealed a loss of genomic 5-methylcytosine associated with the degree of tumor aggressiveness. Paradoxically, this occurs in the context of a growing number of hypermethylated CpG islands of tumor suppressor genes at the most malignant stages of carcinogenesis. We have observed this last phenomenon using two approaches, a candidate gene approach, studying genes with well-known methylation-associated silencing in human tumors, and a mouse cDNA microarray expression analysis after treatment with DNA demethylating drugs. The transition from epithelial to spindle cell morphology is particularly associated with major epigenetic alterations, such as E-cadherin methylation, demethylation of the Snail promoter, and a decrease of the global DNA methylation. Analysis of data obtained from the cDNA microarray strategy led to the identification of new genes that undergo methylation-associated silencing and have growth-inhibitory effects, such as the insulin-like growth factor binding protein-3. Most importantly, all of the above genes were also hypermethylated in human cancer cell lines and primary tumors, underlining the value of the mouse skin carcinogenesis model for the study of aberrant DNA methylation events in cancer cells.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-03-4061
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2004
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
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    Distinct Interactions of EBP1 Isoforms with FBXW7 Elicits Different Functions in Cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 8 ( 2017-04-15), p. 1983-1996
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 8 ( 2017-04-15), p. 1983-1996
    Abstract: The ErbB3 receptor–binding protein EBP1 encodes two alternatively spliced isoforms P48 and P42. While there is evidence of differential roles for these isoforms in tumorigenesis, little is known about their underlying mechanisms. Here, we demonstrate that EBP1 isoforms interact with the SCF-type ubiquitin ligase FBXW7 in distinct ways to exert opposing roles in tumorigenesis. EBP1 P48 bound to the WD domain of FBXW7 as an oncogenic substrate of FBXW7. EBP1 P48 binding sequestered FBXW7α to the cytosol, modulating its role in protein degradation and attenuating its tumor suppressor function. In contrast, EBP1 P42 bound to both the F-box domain of FBXW7 as well as FBXW7 substrates. This adapter function of EBP1 P42 stabilized the interaction of FBXW7 with its substrates and promoted FBXW7-mediated degradation of oncogenic targets, enhancing its overall tumor-suppressing function. Overall, our results establish distinct physical and functional interactions between FBXW7 and EBP1 isoforms, which yield their mechanistically unique isoform-specific functions of EBP1 in cancer. Cancer Res; 77(8); 1983–96. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-16-2246
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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