Publications by authors named "Mitchell Cheung"

28 Publications

  • Page 1 of 1

Novel LRRK2 mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors.

Hum Mol Genet 2021 May 18. Epub 2021 May 18.

Cancer Epigenetics and Signaling Program.

There is irrefutable evidence that germline BAP1 mutations contribute to malignant mesothelioma (MM) susceptibility. However, BAP1 mutations are not found in all cases with evidence of familial MM or in other high-risk cancer families affected by various cancers, including MM. The goal of this study was to use whole genome sequencing (WGS) to determine the frequency and types of germline gene variants occurring in 12 MM patients selected from a series of 141 asbestos-exposed MM patients with a family history of cancer but without a germline BAP1 mutation. WGS was also performed on 2 MM cases, a proband and sibling, from a previously reported family with multiple cases of MM without inheritance of a predisposing BAP1 mutation. Altogether, germline DNA sequencing variants were identified in 20 cancer-related genes in 10 of the 13 probands. Germline indel, splice site, and missense mutations and two large deletions were identified. Among the 13 MM index cases, 6 (46%) exhibited one or more predicted pathogenic mutations. Affected genes encode proteins involved in DNA repair (ATM, ATR, BRCA2, BRIP1, CHEK2, MLH3, MUTYH, POLE, POLE4, POLQ, XRCC1), chromatin modification (ARID1B, DNMT3A, JARID2, SETD1B) or other cellular pathways: LRRK2 (2 cases) and MSH4. Notably, somatic truncating mutation or deletions of LRRK2 were occasionally found in MMs in The Cancer Genome Atlas, and expression of LRRK2 was undetectable or downregulated in a majority of primary MMs and MM cell lines we examined, implying that loss of LRRK2 expression is a newly recognized tumor suppressor alteration in MM.
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http://dx.doi.org/10.1093/hmg/ddab138DOI Listing
May 2021

Kinetic Characterization of ASXL1/2-Mediated Allosteric Regulation of the BAP1 Deubiquitinase.

Mol Cancer Res 2021 Jul 17;19(7):1099-1112. Epub 2021 Mar 17.

The Wistar Institute, Philadelphia, Pennsylvania.

BAP1 is an ubiquitin hydrolase whose deubiquitinase activity is mediated by polycomb group-like protein ASXL2. Cancer-related mutations/deletions lead to loss-of-function by targeting the catalytic ubiquitin C-terminal hydrolase (UCH) or UCH37-like domain (ULD) domains of BAP1, and the latter disrupts binding to ASXL2, an obligate partner for BAP1 enzymatic activity. However, the biochemical and biophysical properties of domains involved in forming the enzymatically active complex are unknown. Here, we report the molecular dynamics, kinetics, and stoichiometry of these interactions. We demonstrate that interactions between BAP1 and ASXL2 are direct, specific, and stable to biochemical and biophysical manipulations as detected by isothermal titration calorimetry (ITC), GST association, and optical biosensor assays. Association of the ASXL2-AB box greatly stimulates BAP1 activity. A stable ternary complex is formed, comprised of the BAP1-UCH, BAP1-ULD, and ASXL2-AB domains. Stoichiometric analysis revealed that one molecule of the ULD domain directly interacts with one molecule of the AB box. Real-time kinetic analysis of the ULD/AB protein complex to the BAP1-UCH domain, based on surface plasmon resonance, indicated that formation of the ULD/AB complex with the UCH domain is a single-step event with fast association and slow dissociation rates. experiments validated in cells that the ASXL-AB box directly regulates BAP1 activity. IMPLICATIONS: Collectively, these data elucidate molecular interactions between specific protein domains regulating BAP1 deubiquitinase activity, thus establishing a foundation for small-molecule approaches to reactivate latent wild-type BAP1 catalytic activity in -mutant cancers.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254751PMC
July 2021

Somatic Epigenetic Silencing of Inactivates Necroptosis and Contributes to Chemoresistance in Malignant Mesothelioma.

Clin Cancer Res 2021 Feb 17;27(4):1200-1213. Epub 2020 Nov 17.

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Purpose: Receptor-interacting protein kinase 3 (RIPK3) phosphorylates effector molecule MLKL to trigger necroptosis. Although RIPK3 loss is seen in several human cancers, its role in malignant mesothelioma is unknown. This study aimed to determine whether RIPK3 functions as a potential tumor suppressor to limit development of malignant mesothelioma.

Experimental Design: RIPK3 expression was examined in 66 malignant mesothelioma tumors and cell lines. Promoter methylation and siRNA studies were performed to assess the mode of silencing in RIPK3-deficient malignant mesothelioma cells. Restoration of RIPK3 expression in RIPK3-negative malignant mesothelioma cells, either by treatment with 5-aza-2'-deoxycytidine or lentiviral expression of cDNA, was performed to assess effects on cell viability, necrosis, and chemosensitization.

Results: Loss of RIPK3 expression was observed in 42/66 (63%) primary malignant mesotheliomas and malignant mesothelioma cell lines, and RT-PCR analysis demonstrated that downregulation occurs at the transcriptional level, consistent with epigenetic silencing. RIPK3-negative malignant mesothelioma cells treated with 5-aza-2'-deoxycytidine resulted in reexpression of RIPK3 and chemosensitization. Ectopic expression of RIPK3 also resulted in chemosensitization and led to necroptosis, the latter demonstrated by phosphorylation of downstream target MLKL and confirmed by rescue experiments. Mining of expression and survival outcomes among patients with malignant mesothelioma available from The Cancer Genome Atlas repository revealed that promoter methylation of is associated with reduced expression and poor prognosis.

Conclusions: These data suggest that RIPK3 acts as a tumor suppressor in malignant mesothelioma by triggering necroptosis and that epigenetic silencing of by DNA methylation impairs necroptosis and contributes to chemoresistance and poor survival in this incurable disease.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887036PMC
February 2021

Inactivation of Cooperates with Losses of and to Drive the Development of Pleural Malignant Mesothelioma in Conditional Mouse Models.

Cancer Res 2019 08 31;79(16):4113-4123. Epub 2019 May 31.

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Pleural malignant mesothelioma is a therapy-resistant cancer affecting the serosal lining of the thoracic cavity. Mutations/deletions of , and are the most frequent genetic lesions in human malignant mesothelioma. We introduced various combinations of these deletions in the pleura of conditional knockout (CKO) mice, focusing on the contribution of loss. While homozygous CKO of , or alone gave rise to few or no malignant mesotheliomas, inactivation of cooperated with loss of either or to drive development of malignant mesothelioma in approximately 20% of double-CKO mice, and a high incidence (22/26, 85%) of malignant mesotheliomas was observed in (triple)-CKO mice. Malignant mesothelioma onset was rapid in triple-CKO mice, with a median survival of only 12 weeks, and malignant mesotheliomas from these mice were consistently high-grade and invasive. Adenoviral-Cre treatment of normal mesothelial cells from CKO mice, but not from mice with knockout of one or any two of these genes, resulted in robust spheroid formation , suggesting that mesothelial cells from mice have stem cell-like potential. RNA-seq analysis of malignant mesotheliomas from triple-CKO mice revealed enrichment of genes transcriptionally regulated by the polycomb repressive complex 2 (PRC2) and others previously implicated in known Bap1-related cellular processes. These data demonstrate that somatic inactivation of , and results in rapid, aggressive malignant mesotheliomas, and that deletion of contributes to tumor development, in part, by loss of PRC2-mediated repression of tumorigenic target genes and by acquisition of stem cell potential, suggesting a potential avenue for therapeutic intervention. SIGNIFICANCE: Combinatorial deletions of , and result in aggressive mesotheliomas, with loss contributing to tumorigenesis by circumventing PRC2-mediated repression of oncogenic target genes.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-4093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697648PMC
August 2019

Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.

J Natl Cancer Inst 2018 12;110(12):1328-1341

Medical Oncology Unit, Ospedale Policlinico San Martino, Genoa, Italy.

Background: The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors.

Methods: We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided.

Results: The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001).

Conclusions: This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.
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http://dx.doi.org/10.1093/jnci/djy171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292796PMC
December 2018

Familial and Somatic Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting Multiple Independent Domains.

Cancer Res 2018 03 28;78(5):1200-1213. Epub 2017 Dec 28.

Wistar Institute, Philadelphia, Pennsylvania.

Deleterious mutations of the ubiquitin carboxy-terminal hydrolase BAP1 found in cancers are predicted to encode inactive truncated proteins, suggesting that loss of enzyme function is a primary tumorigenic mechanism. However, many tumors exhibit missense mutations or in-frame deletions or insertions, often outside the functionally critical UCH domain in this tumor suppressor protein. Thus, precisely how these mutations inactivate BAP1 is unknown. Here, we show how these mutations affect BAP1 interactions with the Polycomb group-like protein, ASXL2, using combinations of computational modeling technology, molecular biology, and reconstitution biochemistry. We found that the BAP1-ASXL2 interaction is direct and high affinity, occurring through the ASXH domain of ASXL2, an obligate partner for BAP1 enzymatic activity. The ASXH domain was the minimal domain for binding the BAP1 ULD domain, and mutations on the surfaces of predicted helices of ASXH abolished BAP1 association and stimulation of BAP1 enzymatic activity. The BAP1-UCH, BAP1-ULD, and ASXH domains formed a cooperative stable ternary complex required for deubiquitination. We defined four classes of alterations in BAP1 outside the UCH domain, each failing to productively recruit ASXH to the wild-type BAP1 catalytic site via the ULD, resulting in loss of BAP1 ubiquitin hydrolase activity. Our results indicate that many BAP1 mutations act allosterically to inhibit ASXH binding, thereby leading to loss of enzyme activity. Small-molecule approaches to reactivate latent wild-type UCH activity of these mutants might be therapeutically viable. Combined computational and biochemical approaches demonstrate that the BAP1-ASXL2 interaction is direct and high affinity and that many mutations act allosterically to inhibit BAP1-ASXL2 binding. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167014PMC
March 2018

, a tumor suppressor gene driving malignant mesothelioma.

Transl Lung Cancer Res 2017 Jun;6(3):270-278

Cancer Biology Program Fox Chase Cancer Center, Philadelphia, PA, USA.

Like cancer generally, malignant mesothelioma (MM) is a genetic disease at the cellular level. DNA copy number analysis of mesothelioma specimens has revealed a number of recurrent sites of chromosomal loss, including 3p21.1, 9p21.3, and 22q12.2. The key inactivated driver genes located at 9p21.1 and 22q12.2 were discovered two decades ago as being the tumor suppressor loci and , respectively. Only relatively recently was the gene determined to be the driver gene at 3p21.1 that is somatically inactivated. In 2011, we reported germline mutations in in two families with a high incidence of mesothelioma and other cancers such as uveal melanoma (UM). As a result of a flurry of research activity over the last 5-6 years, the gene is now firmly linked causally to a novel tumor predisposition syndrome (TPDS) characterized by increased susceptibility to mesothelioma, UM, cutaneous melanoma (CM) and benign melanocytic tumors, as well as several other cancer types. Moreover, results from recent studies with genetically engineered -mutant mouse models and new functional studies have provided intriguing biological insights regarding 's role in tumorigenesis. These and other recent findings offer new possibilities for novel preventative and therapeutic strategies for MM patients.
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http://dx.doi.org/10.21037/tlcr.2017.05.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504107PMC
June 2017

Haploinsufficiency in tumor predisposition syndromes: altered genomic transcription in morphologically normal cells heterozygous for VHL or TSC mutation.

Oncotarget 2017 Mar;8(11):17628-17642

Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease. Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal "one-hit" cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation. Here, we studied histologically non-transformed renal epithelial cells from patients with inherited disorders that predispose to renal tumors, including von Hippel-Lindau (VHL) disease and Tuberous Sclerosis (TSC). As controls, we studied histologically normal cells from non-cancerous renal epithelium of patients with sporadic clear cell renal cell carcinoma (ccRCC). Gene expression analyses of VHLmut/wt or TSC1/2mut/wt versus wild-type (WT) cells revealed transcriptomic alterations previously implicated in the transition to precancerous renal lesions. For example, the gene expression changes in VHLmut/wt cells were consistent with activation of the hypoxia response, associated, in part, with the "Warburg effect". Knockdown of any remaining VHL mRNA using shRNA induced secondary expression changes, such as activation of NFκB and interferon pathways, that are fundamentally important in the development of RCC. We posit that this is a general pattern of hereditary cancer predisposition, wherein haploinsufficiency for VHL or TSC1/2, or potentially other tumor susceptibility genes, is sufficient to promote development of early lesions, while cancer results from inactivation of the remaining normal allele. The gene expression changes identified here are related to the metabolic basis of renal cancer and may constitute suitable targets for early intervention.
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http://dx.doi.org/10.18632/oncotarget.12192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392274PMC
March 2017

Inflammation-Related IL1β/IL1R Signaling Promotes the Development of Asbestos-Induced Malignant Mesothelioma.

Cancer Prev Res (Phila) 2016 05 2;9(5):406-414. Epub 2016 Mar 2.

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111.

Exposure to asbestos is causally associated with the development of malignant mesothelioma, a cancer of cells lining the internal body cavities. Malignant mesothelioma is an aggressive cancer resistant to all current therapies. Once inhaled or ingested, asbestos causes inflammation in and around tissues that come in contact with these carcinogenic fibers. Recent studies suggest that inflammation is a major contributing factor in the development of many types of cancer, including malignant mesothelioma. The NALP3/NLRP3 inflammasome, including the component ASC, is thought to be an important mediator of inflammation in cells that sense extracellular insults, such as asbestos, and activate a signaling cascade resulting in release of mature IL1β and recruitment of inflammatory cells. To determine if inflammasome-mediated inflammation contributes to asbestos-induced malignant mesothelioma, we chronically exposed Asc-deficient mice and wild-type littermates to asbestos and evaluated differences in tumor incidence and latency. The Asc-deficient mice showed significantly delayed tumor onset and reduced malignant mesothelioma incidence compared with wild-type animals. We also tested whether inflammation-related release of IL1β contributes to tumor development in an accelerated mouse model of asbestos-induced malignant mesothelioma. Nf2(+/-);Cdkn2a(+/-) mice exposed to asbestos in the presence of anakinra, an IL1 receptor (IL1R) antagonist, showed a marked delay in the median time of malignant mesothelioma onset compared with similarly exposed mice given vehicle control (33.1 weeks vs. 22.6 weeks, respectively). Collectively, these studies provide evidence for a link between inflammation-related IL1β/IL1R signaling and the development of asbestos-induced malignant mesothelioma. Furthermore, these findings provide rationale for chemoprevention strategies targeting IL1β/IL1R signaling in high-risk, asbestos-exposed populations. Cancer Prev Res; 9(5); 406-14. ©2016 AACR.
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http://dx.doi.org/10.1158/1940-6207.CAPR-15-0347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854753PMC
May 2016

Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations.

Cancer Res 2016 05 19;76(9):2836-44. Epub 2016 Feb 19.

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Individuals harboring inherited heterozygous germline mutations in BAP1 are predisposed to a range of benign and malignant tumor types, including malignant mesothelioma, melanoma, and kidney carcinoma. However, evidence to support a tumor-suppressive role for BAP1 in cancer remains contradictory. To test experimentally whether BAP1 behaves as a tumor suppressor, we monitored spontaneous tumor development in three different mouse models with germline heterozygous mutations in Bap1, including two models in which the knock-in mutations are identical to those reported in human BAP1 cancer syndrome families. We observed spontaneous malignant tumors in 54 of 93 Bap1-mutant mice (58%) versus 4 of 43 (9%) wild-type littermates. All three Bap1-mutant models exhibited a high incidence and similar spectrum of neoplasms, including ovarian sex cord stromal tumors, lung and mammary carcinomas, and spindle cell tumors. Notably, we also observed malignant mesotheliomas in two Bap1-mutant mice, but not in any wild-type animals. We further confirmed that the remaining wild-type Bap1 allele was lost in both spontaneous ovarian tumors and mesotheliomas, resulting in the loss of Bap1 expression. Additional studies revealed that asbestos exposure induced a highly significant increase in the incidence of aggressive mesotheliomas in the two mouse models carrying clinically relevant Bap1 mutations compared with asbestos-exposed wild-type littermates. Collectively, these findings provide genetic evidence that Bap1 is a bona fide tumor suppressor gene and offer key insights into the contribution of carcinogen exposure to enhanced cancer susceptibility. Cancer Res; 76(9); 2836-44. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-3371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873414PMC
May 2016

Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer.

Cancer Res 2016 Jan 30;76(2):206-15. Epub 2015 Dec 30.

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Heritable mutations in the BAP1 tumor suppressor gene predispose individuals to mesothelioma and other cancers. However, a large-scale assessment of germline BAP1 mutation incidence and associated clinical features in mesothelioma patients with a family history of cancer has not been reported. Therefore, we examined the germline BAP1 mutation status of 150 mesothelioma patients with a family history of cancer, 50 asbestos-exposed control individuals with a family history of cancers other than mesothelioma, and 153 asbestos-exposed individuals without familial cancer. No BAP1 alterations were found in control cohorts, but were identified in nine of 150 mesothelioma cases (6%) with a family history of cancer. Alterations among these cases were characterized by both missense and frameshift mutations, and enzymatic activity of BAP1 missense mutants was decreased compared with wild-type BAP1. Furthermore, BAP1 mutation carriers developed mesothelioma at an earlier age that was more often peritoneal than pleural (five of nine) and exhibited improved long-term survival compared to mesothelioma patients without BAP1 mutations. Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas. Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-0295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715907PMC
January 2016

Germline BAP1 mutation in a family with high incidence of multiple primary cancers and a potential gene-environment interaction.

Cancer Lett 2015 Dec 26;369(2):261-5. Epub 2015 Sep 26.

Cancer Biology Program and Genomics Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address:

We report a high-risk cancer family with multiple mesotheliomas, cutaneous melanomas, basal cell carcinomas, and meningiomas segregating with a germline nonsense mutation in BAP1 (c.1938T>A; p.Y646X). Notably, most (four of five) mesotheliomas were peritoneal rather than the usually more common pleural form of the disease, and all five mesothelioma patients also developed second or third primary cancers, including two with meningiomas. Another family member developed both cutaneous melanoma and breast cancer. Two family members had basal cell carcinomas, and six others had melanocytic tumors, including four cutaneous melanomas, one uveal melanoma, and one benign melanocytic tumor. The family resides in a subtropical area, and several members had suspected exposure to asbestos either occupationally or in the home. We hypothesize that the concurrence of a genetic predisposing factor and environmental exposure to asbestos and UV irradiation contributed to the high incidence of multiple cancers seen in this family, specifically mesothelioma and various uveal/skin tumors, respectively.
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http://dx.doi.org/10.1016/j.canlet.2015.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634709PMC
December 2015

An asbestos-exposed family with multiple cases of pleural malignant mesothelioma without inheritance of a predisposing BAP1 mutation.

Cancer Genet 2015 Oct 30;208(10):502-7. Epub 2015 Jul 30.

Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Italy. Electronic address:

We report a family with domestic exposure to asbestos and diagnosis of multiple cancers, including eight pleural malignant mesotheliomas and several other lung or pleural tumors. DNA sequence analysis revealed no evidence for an inherited mutation of BAP1. Sequence analysis of other potentially relevant genes, including TP53, CDKN2A, and BARD1, also revealed no mutation. DNA microarray analysis of tissue from two mesotheliomas revealed multiple genomic imbalances, including consistent losses of overlapping segments in 2q, 6q, 9p, 14q, 15q, and 22q, but no losses of chromosome 3 harboring the BAP1 locus. However, the results of immunohistochemical analysis demonstrated loss of nuclear BAP1 staining in three of six mesotheliomas tested, suggesting that somatic alterations of BAP1 occurred in a subset of tumors from this family. Since mesothelioma could be confirmed in only a single generation, domestic exposure to asbestos may be the predominant cause of mesothelioma in this family. Given the existence of unspecified malignant pleural tumors and lung cancers in a prior generation, we discuss the possibility that some other tumor susceptibility or modifier gene(s) may contribute to the high incidence of mesothelioma in this family. Because the incidence of mesothelioma in this family is higher than that expected even in workers heavily exposed to asbestos, we conclude that both asbestos exposure and genetic factors have played a role in the high rate of mesothelioma and potentially other pleural or lung cancers seen in this family. 
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http://dx.doi.org/10.1016/j.cancergen.2015.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608746PMC
October 2015

Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma.

BMC Cancer 2015 May 8;15:376. Epub 2015 May 8.

Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Background: The development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models.

Methods: We established primary mesothelioma cultures from pleural and ascitic fluids of five patients with advanced mesothelioma. Electron microscopy and immunohistochemistry (IHC) confirmed their mesothelial origin. Patient derived xenografts were generated by injecting the cells in nude or SCID mice, and malignant potential of the cells was analyzed by soft agar colony assay. Molecular profiles of the primary patient tumors, early passage cell cultures, and patient derived xenografts were assessed using mutational analysis, fluorescence in situ hybridization (FISH) analysis and IHC.

Results: Primary cultures from all five tumors exhibited morphologic and IHC features consistent to those of mesothelioma cells. Mutations of BAP1 and CDKN2A were each detected in four tumors. BAP1 mutation was associated with the lack of expression of BAP1 protein. Three cell cultures, all of which were derived from BAP1 mutant primary tumors, exhibited anchorage independent growth and also formed tumors in mice, suggesting that BAP1 loss may enhance tumor growth in vivo. Both early passage cell cultures and mouse xenograft tumors harbored BAP1 mutations and CDKN2A deletions identical to those found in the corresponding primary patient tumors.

Conclusions: The mesothelioma patient derived tumor xenografts with mutational alterations that mimic those observed in patient tumors which we established can be used for preclinical development of novel drug regimens and for studying the functional aspects of BAP1 biology in mesothelioma.
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http://dx.doi.org/10.1186/s12885-015-1362-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431029PMC
May 2015

Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma.

Cancer Res 2014 Aug 13;74(16):4388-97. Epub 2014 Jun 13.

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germline-inactivating mutations of BAP1 predispose to mesothelioma and certain other cancers. However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers are not known. To address these questions experimentally, we generated a Bap1(+/-) knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. Bap1(+/-) mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than wild-type (WT) littermates (73% vs. 32%, respectively). Furthermore, mesotheliomas arose at an accelerated rate in Bap1(+/-) mice than in WT animals (median survival, 43 weeks vs. 55 weeks after initial exposure, respectively) and showed increased invasiveness and proliferation. No spontaneous mesotheliomas were seen in unexposed Bap1(+/-) mice followed for up to 87 weeks of age. Mesothelioma cells from Bap1(+/-) mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in WT mice, mesotheliomas from Bap1(+/-) mice did not require homozygous loss of Cdkn2a. However, normal mesothelial cells and mesothelioma cells from Bap1(+/-) mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1(+/-) mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb. Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-1328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165574PMC
August 2014

Copy neutral loss of heterozygosity in 20q in chronic lymphocytic leukemia/small lymphocytic lymphoma.

Cancer Genet 2014 Mar 15;207(3):98-102. Epub 2014 Feb 15.

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA; Clinical Cytogenomics Laboratory, Fox Chase Cancer Center, Philadelphia, PA, USA. Electronic address:

Single nucleotide polymorphism (SNP)-based chromosome microarray analysis was used to uncover copy neutral loss of heterozygosity (LOH) in the long arm of chromosome 20 in blood or bone marrow specimens from three patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). All three patients presented with lymph node enlargement. Whereas one of the patients has had a complicated clinical course, the other two have a more indolent disease. Sequence analysis of the tumor suppressor gene ASXL1, which is located in 20q and is commonly mutated in malignant myeloid diseases and occasionally in CLL/SLL specimens, revealed no mutations in our three patients with copy neutral LOH in 20q. The possible contribution of other imprinted microRNAs and antisense genes residing in 20q to the pathogenesis of a subset of CLL/SLL patients is discussed. These findings illustrate the value of SNP arrays for the detection of novel recurrent genomic alterations that may contribute to CLL/SLL onset or progression.
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http://dx.doi.org/10.1016/j.cancergen.2014.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010307PMC
March 2014

Further evidence for germline BAP1 mutations predisposing to melanoma and malignant mesothelioma.

Cancer Genet 2013 May;206(5):206-10

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.

We describe a new family with a novel germline BAP1 nonsense mutation, c.723T>G, which leads to a predicted truncated protein, p.Y241*, or nonsense-mediated decay of the BAP1 mRNA. The proband had uveal melanoma (UM), and his paternal family has a remarkable history of multiple cancers. The proband's father had both pleural malignant mesothelioma (MM) and cutaneous melanoma (CM); a paternal uncle had lung cancer, CM, and UM; and a grandmother had CM. The findings in this family provide further support for the existence of a BAP1 cancer syndrome that predisposes to MM, various melanocytic neoplasms, and potentially other cancers. The fact that several members of the family manifested two or more different types of cancer suggests widespread BAP1-related tumor susceptibility targeting tissues of multiple organs. In addition, a review of BAP1 cancer syndrome families reported to date indicates that the location of the BAP1 mutation does not have any bearing on the spectrum of cancer types observed, either for mesothelial or melanocytic tumors.
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http://dx.doi.org/10.1016/j.cancergen.2013.05.018DOI Listing
May 2013

NF-κB inhibition by bortezomib permits IFN-γ-activated RIP1 kinase-dependent necrosis in renal cell carcinoma.

Mol Cancer Ther 2013 Aug 8;12(8):1568-78. Epub 2013 May 8.

Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA, USA.

Advanced renal cell carcinoma (RCC) is an invariably fatal cancer. Currently, small-molecule inhibitors that target cell growth, angiogenesis, or nutrient-sensing pathways represent the primary pharmacologic interventions for this disease, but these inhibitors only delay tumor progression and are not curative. The cytokine IFN-γ showed the potential to provide lasting remission in several phase I/II trials for advanced RCCs, but subsequent trials, including a multicenter phase III study using IFN-γ as a monotherapy for RCCs, were less promising. Notably, these trials were designed to exploit the indirect immunomodulatory effects of IFN-γ, whereas its direct antitumor properties--including its ability to trigger programmed cell death in tumors-remain mostly untapped. Here, we show that the proteasome inhibitor bortezomib (PS-341, Velcade) sensitizes otherwise resistant RCC cells to direct necrotic death by IFN-γ. Mechanistically, we show that bortezomib functions, at least in part, by inhibiting prosurvival NF-κB signaling. In the absence of this signal, IFN-γ triggers programmed necrosis (or "necroptosis") dependent on the kinase RIP1. When taken together with the observation that NF-κB signaling is elevated in RCCs, these results provide rationale for the combined use of IFN-γ and bortezomib in the treatment of metastatic RCCs.
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http://dx.doi.org/10.1158/1535-7163.MCT-12-1010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746800PMC
August 2013

Diverse mechanisms of AKT pathway activation in human malignancy.

Curr Cancer Drug Targets 2013 Mar;13(3):234-44

Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.

AKT/PKB (Protein Kinase B) are central proteins mediating signals from receptor tyrosine kinases and phosphatidylinositol 3-kinase. AKT kinases are involved in a number of important cellular processes including cell proliferation and survival, cell size in response to nutrient availability, tumor invasion/metastasis, and angiogenesis.Various components of the AKT signaling pathway are encoded by tumor suppressor genes and oncogenes whose loss or activation, respectively, plays an important role in tumorigenesis. The growing body of evidence connecting deregulated AKT signaling with sporadic human cancers and inherited cancer predisposition syndromes is discussed. We also highlight new findings regarding the involvement of activating mutations of AKT1, AKT2, and AKT3 in somatic overgrowth disorders: Proteus syndrome, hypoglycemia with hypertrophy, and hemimegalencephaly, respectively. In addition, we review recent literature documenting the various ways the AKT signaling pathway is activated in human cancers and consequences for molecularly targeted therapies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678724PMC
http://dx.doi.org/10.2174/1568009611313030002DOI Listing
March 2013

Germline BAP1 mutations predispose to malignant mesothelioma.

Nat Genet 2011 Aug 28;43(10):1022-5. Epub 2011 Aug 28.

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.
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http://dx.doi.org/10.1038/ng.912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184199PMC
August 2011

Upregulation of DLX5 promotes ovarian cancer cell proliferation by enhancing IRS-2-AKT signaling.

Cancer Res 2010 Nov 2;70(22):9197-206. Epub 2010 Nov 2.

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

The distal-less homeobox gene (dlx) 5 encodes a transcription factor that controls jaw formation and appendage differentiation during embryonic development. We had previously found that Dlx5 is overexpressed in an Akt2 transgenic model of T-cell lymphoma. To investigate if DLX5 is involved in human cancer, we screened its expression in the NCI 60 cancer cell line panel. DLX5 was frequently upregulated in cell lines derived from several tumor types, including ovarian cancer. We next validated its upregulation in primary ovarian cancer specimens. Stable knockdown of DLX5 by lentivirus-mediated transduction of short hairpin RNA (shRNA) resulted in reduced proliferation of ovarian cancer cells due to inhibition of cell cycle progression in connection with the downregulation of cyclins A, B1, D1, D2, and E, and decreased phosphorylation of AKT. Cell proliferation resumed following introduction of a DLX5 cDNA harboring wobbled mutations at the shRNA-targeting sites. Cell proliferation was also rescued by transduction of a constitutively active form of AKT. Intriguingly, downregulation of IRS-2 and MET contributed to the suppression of AKT signaling. Moreover, DLX5 was found to directly bind to the IRS-2 promoter and augmented its transcription. Knockdown of DLX5 in xenografts of human ovarian cancer cells resulted in markedly diminished tumor size. In addition, DLX5 was found to cooperate with HRAS in the transformation of human ovarian surface epithelial cells. Together, these data suggest that DLX5 plays a significant role in the pathogenesis of some ovarian cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-1568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018149PMC
November 2010

Onconase responsive genes in human mesothelioma cells: implications for an RNA damaging therapeutic agent.

BMC Cancer 2010 Feb 5;10:34. Epub 2010 Feb 5.

Cancer Genetics & Signaling Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.

Background: Onconase represents a new class of RNA-damaging drugs. Mechanistically, Onconase is thought to internalize, where it degrades intracellular RNAs such as tRNA and double-stranded RNA, and thereby suppresses protein synthesis. However, there may be additional or alternative mechanism(s) of action.

Methods: In this study, microarray analysis was used to compare gene expression profiles in untreated human malignant mesothelioma (MM) cell lines and cells exposed to 5 microg/ml Onconase for 24 h. A total of 155 genes were found to be regulated by Onconase that were common to both epithelial and biphasic MM cell lines. Some of these genes are known to significantly affect apoptosis (IL-24, TNFAIP3), transcription (ATF3, DDIT3, MAFF, HDAC9, SNAPC1) or inflammation and the immune response (IL-6, COX-2). RT-PCR analysis of selected up- or down-regulated genes treated with varying doses and times of Onconase generally confirmed the expression array findings in four MM cell lines.

Results: Onconase treatment consistently resulted in up-regulation of IL-24, previously shown to have tumor suppressive activity, as well as ATF3 and IL-6. Induction of ATF3 and the pro-apoptotic factor IL-24 by Onconase was highest in the two most responsive MM cell lines, as defined by DNA fragmentation analysis. In addition to apoptosis, gene ontology analysis indicated that pathways impacted by Onconase include MAPK signaling, cytokine-cytokine-receptor interactions, and Jak-STAT signaling.

Conclusions: These results provide a broad picture of gene activity after treatment with a drug that targets small non-coding RNAs and contribute to our overall understanding of MM cell response to Onconase as a therapeutic strategy. The findings provide insights regarding mechanisms that may contribute to the efficacy of this novel drug in clinical trials of MM patients who have failed first line chemotherapy or radiation treatment.
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http://dx.doi.org/10.1186/1471-2407-10-34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829496PMC
February 2010

Akt3 and mutant V600E B-Raf cooperate to promote early melanoma development.

Cancer Res 2008 May;68(9):3429-39

Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

B-Raf is the most mutated gene in melanoma; however, the mechanism through which it promotes early melanomas remains uncertain. Most nevi contain activated (V600E)B-Raf but few develop into melanoma, and expression in melanocytes is inhibitory with low protein levels present in surviving cells, suggesting unknown cooperative oncogenic events are necessary for melanoma development. Because many melanomas have (V600E)B-Raf and active Akt3, it is possible that these proteins cooperatively facilitate melanocyte transformation. In this study, Akt3 is shown to phosphorylate (V600E)B-Raf to lower its activity as well as that of the downstream mitogen-activated protein kinase (MAPK) pathway to levels promoting early melanoma development. Expression of active Akt3 in early melanoma cells containing (V600E)B-Raf reduced MAPK signaling and promoted anchorage-independent growth. Furthermore, expression of both (V600E)B-Raf and active Akt3 in melanocytes promoted a transformed phenotype. Mechanistically, aberrant Akt3 activity in early melanomas serves to phosphorylate Ser(364) and Ser(428) on (V600E)B-Raf to reduce activity of (V600E)B-Raf to levels that promote rather than inhibit proliferation, which aids melanocytic transformation. Inhibition of (V600E)B-Raf or Akt3 in advanced melanoma cells in which both pathways were active reduced anchorage-independent growth and tumor development in a cooperatively acting manner. Inhibition of Akt3 alone in these cells led to increased MAPK signaling. In summary, these results suggest that activating B-Raf mutations initially promote nevi development, but the resulting high, intense activation of the MAPK pathway inhibits further tumor progression requiring Akt3 activation to bypass this barrier and aid melanoma development.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-5867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603082PMC
May 2008

RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model.

Clin Cancer Res 2007 Jul;13(14):4261-70

Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

Purpose: mTOR (mammalian target of rapamycin) plays a central role in regulating cell growth and cell cycle progression and is regarded as a promising therapeutic target. We examined whether mTOR inhibition by RAD001 (everolimus) is therapeutically efficacious in the treatment of ovarian cancer as a single agent and in combination with cisplatin.

Experimental Design: Using four human ovarian cancer cell lines, we determined the effect of RAD001 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Western blot, and apoptosis assays. We evaluated the association between phospho-AKT/mTOR activity and RAD001 sensitivity. We also determined the effect of RAD001 on tumor growth and malignancy using mice inoculated with human ovarian cancer cells.

Results: RAD001 markedly inhibited cell proliferation of human ovarian carcinoma cells with high AKT activity (OVCAR10 and SKOV-3), but the effect was minimal in cells with low AKT activity (OVCAR4 and OVCAR5). Sensitivity to RAD001 was independent of p53 expression. RAD001 inhibited the phosphorylation of downstream 4E-BP1 and p70S6 kinase and attenuated the expression of Myc. RAD001 also attenuated the expression of HIF-1 alpha and vascular endothelial growth factor, important factors in angiogenesis and tumor invasiveness. RAD001 enhanced cisplatin-induced apoptosis in cells with high AKT/mTOR activity, with minimal effect in cells with low AKT-mTOR activity. Mouse xenografts of SKOV-3 cells revealed that RAD001 inhibits tumor growth, angiogenesis, and i.p. dissemination and ascites production and prolongs survival. Moreover, treatment with RAD001 significantly enhanced the therapeutic efficacy of cisplatin in vivo.

Conclusion: These results indicate that RAD001 could have therapeutic efficacy in human ovarian cancers with hyperactivated AKT/mTOR signaling.
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http://dx.doi.org/10.1158/1078-0432.CCR-06-2770DOI Listing
July 2007

Deregulated Akt3 activity promotes development of malignant melanoma.

Cancer Res 2004 Oct;64(19):7002-10

Department of Pharmacology, The Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033, USA.

Malignant melanoma is the skin cancer with the most significant impact on man, carrying the highest risk of death from metastasis. Both incidence and mortality rates continue to rise each year, with no effective long-term treatment on the horizon. In part, this reflects lack of identification of critical genes involved and specific therapies targeted to correct these defects. We report that selective activation of the Akt3 protein promotes cell survival and tumor development in 43 to 60% of nonfamilial melanomas. The predominant Akt isoform active in melanomas was identified by showing that small interfering RNA (siRNA) against only Akt3, and not Akt1 or Akt2, lowered the amount of phosphorylated (active) Akt in melanoma cells. The amount of active Akt3 increased progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Mechanisms of Akt3 deregulation occurred through a combination of overexpression of Akt3 accompanying copy number increases of the gene and decreased PTEN protein function occurring through loss or haploinsufficiency of the PTEN gene. Targeted reduction of Akt3 activity with siRNA or by expressing active PTEN protein stimulated apoptotic signaling, which reduced cell survival by increasing apoptosis rates thereby inhibiting melanoma tumor development. Identifying Akt3 as a selective target in melanoma cells provides new therapeutic opportunities for patients in the advanced stages of this disease.
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http://dx.doi.org/10.1158/0008-5472.CAN-04-1399DOI Listing
October 2004

Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent.

J Biol Chem 2004 Jul 18;279(29):29930-7. Epub 2004 May 18.

Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome with manifestations that can include seizures, mental retardation, autism, and tumors in the brain, retina, kidney, heart, and skin. The products of the TSC1 and TSC2 genes, hamartin and tuberin, respectively, heterodimerize and inhibit the mammalian target of rapamycin (mTOR). We found that tuberin expression increases p42/44 MAPK phosphorylation and B-Raf kinase activity. Short interfering RNA down-regulation of tuberin decreased the p42/44 MAPK phosphorylation and B-Raf activity. Expression of Rheb, the target of the GTPase-activating domain of tuberin, inhibited wild-type B-Raf kinase but not activated forms of B-Raf. The interaction of endogenous Rheb with B-Raf was enhanced by serum and by Ras overexpression. A farnesylation-defective mutant of Rheb co-immunoprecipitated with and inhibited B-Raf but did not activate ribosomal protein S6 kinase, indicating that farnesylation is not required for B-Raf inhibition by Rheb and that B-Raf inhibition and S6 kinase activation are separable activities of Rheb. Consistent with this, inhibition of B-Raf and p42/44 MAPK by Rheb was resistant to rapamycin in contrast to Rheb activation of S6 kinase, which is rapamycin-sensitive. Taken together these data demonstrate that inhibition of B-Raf kinase via Rheb is an mTOR-independent function of tuberin.
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http://dx.doi.org/10.1074/jbc.M402591200DOI Listing
July 2004

Loss of PTEN promotes tumor development in malignant melanoma.

Cancer Res 2003 Jun;63(11):2881-90

Department of Pharmacology, The Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033, USA.

Loss of tumor suppressor genes on chromosome 10 plays an important role in the development of 30-60% of melanomas; however, the identity of these genes and the mechanisms by which loss of these genes leads to tumor formation remain uncertain. The phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is one of the genes on chromosome 10 whose of which the loss or inactivation may play an important role in melanoma tumorigenesis, but functional studies directly demonstrating PTEN involvement in melanomas are necessary to confirm this role. To determine the biological importance of PTEN loss in melanomas, we established a novel model in which an intact chromosome 10 was transferred into melanoma cells lacking PTEN protein to express the protein at normal physiological levels and to measure the consequent effects on melanoma tumorigenesis. PTEN expression in these cells retarded tumor development in mice unless, by analogy with loss of heterozygosity, the PTEN gene was deleted or inactivated during tumor formation. Mechanistically, PTEN loss led to the activation of Akt, which consequently down-regulated the apoptotic pathway of melanoma cells. In contrast, expression of PTEN attenuated Akt activation, thereby increasing sensitivity to apoptotic stimuli in cell culture and in vivo in animal models. This model demonstrated that PTEN loss is critical for melanoma tumorigenesis and allowed a dissection of the underlying mechanism by which PTEN loss facilitated melanoma tumor development. In summary, loss of PTEN reduces apoptosis and promotes cell survival, thereby favoring melanoma tumor formation. Thus, these observations provide an etiological basis for PTEN loss during the genesis of sporadic melanomas.
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June 2003
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