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ROCK-nmMyoII, Notch and gene-dosage link epithelial morphogenesis with cell fate in the pancreatic endocrine-progenitor niche.
Bankaitis ED, Bechard ME, Gu G, Magnuson MA, Wright CVE
(2018) Development 145:
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Movement, Endocrine Cells, Gene Dosage, Mice, Mice, Transgenic, Nerve Tissue Proteins, Organogenesis, Pancreas, Receptors, Notch, Stem Cells, Transcriptional Activation, rho-Associated Kinases
Show Abstract · Added August 24, 2018
During mouse pancreas organogenesis, endocrine cells are born from progenitors residing in an epithelial plexus niche. After a period in a lineage-primed state, progenitors become endocrine committed via upregulation of We find that the to transition is associated with distinct stages of an epithelial egression process: narrowing the apical surface of the cell, basalward cell movement and eventual cell-rear detachment from the apical lumen surface to allow clustering as nascent islets under the basement membrane. Apical narrowing, basalward movement and transcriptional upregulation still occur without Neurog3 protein, suggesting that morphogenetic cues deployed within the plexus initiate endocrine commitment upstream or independently of Neurog3. Neurog3 is required for cell-rear detachment and complete endocrine-cell birth. The ROCK-nmMyoII pathway coordinates epithelial-cell morphogenesis and the progression through -expressing states. NmMyoII is necessary for apical narrowing, basalward cell displacement and upregulation, but all three are limited by ROCK activity. We propose that ROCK-nmMyoII activity, gene-dose and Notch signaling integrate endocrine fate allocation with epithelial plexus growth and morphogenesis, representing a feedback control circuit that coordinates morphogenesis with lineage diversification in the endocrine-birth niche.
© 2018. Published by The Company of Biologists Ltd.
2 Communities
2 Members
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15 MeSH Terms
Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma.
McFadden DG, Politi K, Bhutkar A, Chen FK, Song X, Pirun M, Santiago PM, Kim-Kiselak C, Platt JT, Lee E, Hodges E, Rosebrock AP, Bronson RT, Socci ND, Hannon GJ, Jacks T, Varmus H
(2016) Proc Natl Acad Sci U S A 113: E6409-E6417
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Animals, Carcinogens, Cell Transformation, Neoplastic, DNA Copy Number Variations, DNA Mutational Analysis, Disease Models, Animal, ErbB Receptors, Gene Dosage, Genes, myc, Genes, ras, Genome-Wide Association Study, Lung Neoplasms, Mice, Mice, Transgenic, Mutation, Point Mutation, ROC Curve, Whole Exome Sequencing
Show Abstract · Added April 26, 2017
Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.
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20 MeSH Terms
Homeostatic Responses Regulate Selfish Mitochondrial Genome Dynamics in C. elegans.
Gitschlag BL, Kirby CS, Samuels DC, Gangula RD, Mallal SA, Patel MR
(2016) Cell Metab 24: 91-103
MeSH Terms: Animals, Caenorhabditis elegans, DNA, Mitochondrial, Gene Deletion, Gene Dosage, Genome, Mitochondrial, Homeostasis, Mitochondrial Dynamics, Mutation, RNA Interference, Transcription, Genetic, Unfolded Protein Response
Show Abstract · Added March 21, 2018
Mutant mitochondrial genomes (mtDNA) can be viewed as selfish genetic elements that persist in a state of heteroplasmy despite having potentially deleterious metabolic consequences. We sought to study regulation of selfish mtDNA dynamics. We establish that the large 3.1-kb deletion-bearing mtDNA variant uaDf5 is a selfish genome in Caenorhabditis elegans. Next, we show that uaDf5 mutant mtDNA replicates in addition to, not at the expense of, wild-type mtDNA. These data suggest the existence of a homeostatic copy-number control that is exploited by uaDf5 to "hitchhike" to high frequency. We also observe activation of the mitochondrial unfolded protein response (UPR(mt)) in uaDf5 animals. Loss of UPR(mt) causes a decrease in uaDf5 frequency, whereas its constitutive activation increases uaDf5 levels. UPR(mt) activation protects uaDf5 from mitophagy. Taken together, we propose that mtDNA copy-number control and UPR(mt) represent two homeostatic response mechanisms that play important roles in regulating selfish mitochondrial genome dynamics.
Copyright © 2016 Elsevier Inc. All rights reserved.
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1 Members
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12 MeSH Terms
A transcription factor network controls cell migration and fate decisions in the developing zebrafish pineal complex.
Khuansuwan S, Clanton JA, Dean BJ, Patton JG, Gamse JT
(2016) Development 143: 2641-50
MeSH Terms: Animals, Body Patterning, Cell Count, Cell Lineage, Cell Movement, Gene Dosage, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Habenula, Larva, Mosaicism, Mutation, Neurons, Pineal Gland, Retinal Rod Photoreceptor Cells, Transcription Factors, Zebrafish, Zebrafish Proteins
Show Abstract · Added August 4, 2017
The zebrafish pineal complex consists of four cell types (rod and cone photoreceptors, projection neurons and parapineal neurons) that are derived from a single pineal complex anlage. After specification, parapineal neurons migrate unilaterally away from the rest of the pineal complex whereas rods, cones and projection neurons are non-migratory. The transcription factor Tbx2b is important for both the correct number and migration of parapineal neurons. We find that two additional transcription factors, Flh and Nr2e3, negatively regulate parapineal formation. Flh induces non-migratory neuron fates and limits the extent of parapineal specification, in part by activation of Nr2e3 expression. Tbx2b is positively regulated by Flh, but opposes Flh action during specification of parapineal neurons. Loss of parapineal neuron specification in Tbx2b-deficient embryos can be partially rescued by loss of Nr2e3 or Flh function; however, parapineal migration absolutely requires Tbx2b activity. We conclude that cell specification and migration in the pineal complex are regulated by a network of at least three transcription factors.
© 2016. Published by The Company of Biologists Ltd.
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18 MeSH Terms
Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and β-Cell Function.
Henley KD, Stanescu DE, Kropp PA, Wright CVE, Won KJ, Stoffers DA, Gannon M
(2016) Cell Rep 15: 2637-2650
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Count, Cell Differentiation, Embryo, Mammalian, Gene Dosage, Gene Expression Regulation, Developmental, Gene Ontology, Gene Regulatory Networks, Glucose, Hepatocyte Nuclear Factor 6, Heterozygote, Homeodomain Proteins, Homeostasis, Insulin-Secreting Cells, Mice, Multigene Family, Nerve Tissue Proteins, Stem Cells, Trans-Activators, Weaning
Show Abstract · Added July 5, 2016
Pdx1 and Oc1 are co-expressed in multipotent pancreatic progenitors and regulate the pro-endocrine gene Neurog3. Their expression diverges in later organogenesis, with Oc1 absent from hormone+ cells and Pdx1 maintained in mature β cells. In a classical genetic test for cooperative functional interactions, we derived mice with combined Pdx1 and Oc1 heterozygosity. Endocrine development in double-heterozygous pancreata was normal at embryonic day (E)13.5, but defects in specification and differentiation were apparent at E15.5, the height of the second wave of differentiation. Pancreata from double heterozygotes showed alterations in the expression of genes crucial for β-cell development and function, decreased numbers and altered allocation of Neurog3-expressing endocrine progenitors, and defective endocrine differentiation. Defects in islet gene expression and β-cell function persisted in double heterozygous neonates. These results suggest that Oc1 and Pdx1 cooperate prior to their divergence, in pancreatic progenitors, to allow for proper differentiation and functional maturation of β cells.
Published by Elsevier Inc.
1 Communities
2 Members
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21 MeSH Terms
Genetic and chromosomal alterations in Kenyan Wilms Tumor.
Lovvorn HN, Pierce J, Libes J, Li B, Wei Q, Correa H, Gouffon J, Clark PE, Axt JR, Hansen E, Newton M, O'Neill JA, Kenyan Wilms Tumor Consortium
(2015) Genes Chromosomes Cancer 54: 702-15
MeSH Terms: Child, Preschool, Chromosome Aberrations, Cohort Studies, Female, Gene Dosage, Genes, Wilms Tumor, High-Throughput Nucleotide Sequencing, Humans, Kenya, Kidney Neoplasms, Male, Mutation, Proto-Oncogene Proteins p21(ras), Wilms Tumor
Show Abstract · Added October 1, 2015
Wilms tumor (WT) is the most common childhood kidney cancer worldwide and poses a cancer health disparity to black children of sub-Saharan African ancestry. Although overall survival from WT at 5 years exceeds 90% in developed countries, this pediatric cancer is alarmingly lethal in sub-Saharan Africa and specifically in Kenya (36% survival at 2 years). Although multiple barriers to adequate WT therapy contribute to this dismal outcome, we hypothesized that a uniquely aggressive and treatment-resistant biology compromises survival further. To explore the biologic composition of Kenyan WT (KWT), we completed a next generation sequencing analysis targeting 10 WT-associated genes and evaluated whole-genome copy number variation. The study cohort was comprised of 44 KWT patients and their specimens. Fourteen children are confirmed dead at 2 years and 11 remain lost to follow-up despite multiple tracing attempts. TP53 was mutated most commonly in 11 KWT specimens (25%), CTNNB1 in 10 (23%), MYCN in 8 (18%), AMER1 in 5 (11%), WT1 and TOP2A in 4 (9%), and IGF2 in 3 (7%). Loss of heterozygosity (LOH) at 17p, which covers TP53, was detected in 18% of specimens examined. Copy number gain at 1q, a poor prognostic indicator of WT biology in developed countries, was detected in 32% of KWT analyzed, and 89% of these children are deceased. Similarly, LOH at 11q was detected in 32% of KWT, and 80% of these patients are deceased. From this genomic analysis, KWT biology appears uniquely aggressive and treatment-resistant.
© 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.
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14 MeSH Terms
Genomic investigation of etiologic heterogeneity: methodologic challenges.
Begg CB, Seshan VE, Zabor EC, Furberg H, Arora A, Shen R, Maranchie JK, Nielsen ME, Rathmell WK, Signoretti S, Tamboli P, Karam JA, Choueiri TK, Hakimi AA, Hsieh JJ
(2014) BMC Med Res Methodol 14: 138
MeSH Terms: Biomarkers, Tumor, Carcinoma, Renal Cell, DNA Methylation, Female, Gene Dosage, Gene Expression Profiling, Genetic Predisposition to Disease, Genome, Human, Humans, Kidney Neoplasms, Male, Middle Aged, Risk Factors, Sex Factors
Show Abstract · Added October 17, 2015
BACKGROUND - The etiologic heterogeneity of cancer has traditionally been investigated by comparing risk factor frequencies within candidate sub-types, defined for example by histology or by distinct tumor markers of interest. Increasingly tumors are being profiled for molecular features much more extensively. This greatly expands the opportunities for defining distinct sub-types. In this article we describe an exploratory analysis of the etiologic heterogeneity of clear cell kidney cancer. Data are available on the primary known risk factors for kidney cancer, while the tumors are characterized on a genome-wide basis using expression, methylation, copy number and mutational profiles.
METHODS - We use a novel clustering strategy to identify sub-types. This is accomplished independently for the expression, methylation and copy number profiles. The goals are to identify tumor sub-types that are etiologically distinct, to identify the risk factors that define specific sub-types, and to endeavor to characterize the key genes that appear to represent the principal features of the distinct sub-types.
RESULTS - The analysis reveals strong evidence that gender represents an important factor that distinguishes disease sub-types. The sub-types defined using expression data and methylation data demonstrate considerable congruence and are also clearly correlated with mutations in important cancer genes. These sub-types are also strongly correlated with survival. The complexity of the data presents many analytical challenges including, prominently, the risk of false discovery.
CONCLUSIONS - Genomic profiling of tumors offers the opportunity to identify etiologically distinct sub-types, paving the way for a more refined understanding of cancer etiology.
0 Communities
1 Members
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14 MeSH Terms
Comprehensive molecular profiling of lung adenocarcinoma.
Cancer Genome Atlas Research Network
(2014) Nature 511: 543-50
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Cell Cycle Proteins, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Genomics, Humans, Lung Neoplasms, Male, Molecular Typing, Mutation, Oncogenes, Sex Factors, Transcriptome
Show Abstract · Added August 8, 2016
Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.
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15 MeSH Terms
Oncogenic protein MTBP interacts with MYC to promote tumorigenesis.
Grieb BC, Gramling MW, Arrate MP, Chen X, Beauparlant SL, Haines DS, Xiao H, Eischen CM
(2014) Cancer Res 74: 3591-602
MeSH Terms: 3T3 Cells, ATPases Associated with Diverse Cellular Activities, Animals, Apoptosis, Breast Neoplasms, Carrier Proteins, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, DNA Helicases, Female, Gene Dosage, HEK293 Cells, Humans, Mice, Mice, Nude, Protein Binding, Proto-Oncogene Proteins c-mdm2, Proto-Oncogene Proteins c-myc, Rats
Show Abstract · Added May 27, 2014
Despite its involvement in most human cancers, MYC continues to pose a challenge as a readily tractable therapeutic target. Here we identify the MYC transcriptional cofactors TIP48 and TIP49 and MYC as novel binding partners of Mdm2-binding protein (MTBP), a functionally undefined protein that we show is oncogenic and overexpressed in many human cancers. MTBP associated with MYC at promoters and increased MYC-mediated transcription, proliferation, neoplastic transformation, and tumor development. In breast cancer specimens, we determined overexpression of both MYC and MTBP was associated with a reduction in 10-year patient survival compared with MYC overexpression alone. MTBP was also frequently co-amplified with MYC in many human cancers. Mechanistic investigations implicated associations with TIP48/TIP49 as well as MYC in MTBP function in cellular transformation and the growth of human breast cancer cells. Taken together, our findings show MTBP functions with MYC to promote malignancy, identifying this protein as a novel general therapeutic target in human cancer.
©2014 American Association for Cancer Research.
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20 MeSH Terms
Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes.
Haas DW, Kwara A, Richardson DM, Baker P, Papageorgiou I, Acosta EP, Morse GD, Court MH
(2014) J Antimicrob Chemother 69: 2175-82
MeSH Terms: Adult, African Continental Ancestry Group, Anti-HIV Agents, Benzoxazines, Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B6, Cytochrome P-450 CYP2B6 Inducers, European Continental Ancestry Group, Female, Gene Dosage, Glucuronosyltransferase, HIV Infections, HIV-1, Humans, Male, Polymorphism, Single Nucleotide, Prospective Studies, Reverse Transcriptase Inhibitors, Secondary Metabolism
Show Abstract · Added March 13, 2015
OBJECTIVES - Efavirenz is widely prescribed for HIV-1 infection, and CYP2B6 polymorphisms 516G→T and 983T→C define efavirenz slow metabolizer genotypes. To identify genetic predictors of higher plasma efavirenz concentrations beyond these two common functional alleles, we characterized associations with mid-dosing interval efavirenz concentrations in 84 HIV-infected adults, all carrying two copies of these major loss-of-function CYP2B6 alleles.
METHODS - Study participants had been randomized to efavirenz-containing regimens in prospective clinical trials and had available plasma efavirenz assay data. Analyses focused on secondary metabolism pathway polymorphisms CYP2A6 -48T→G (rs28399433), UGT2B7 735A→G (rs28365062) and UGT2B7 802T→C (rs7439366). Exploratory analyses also considered 196 polymorphisms and 8 copy number variants in 41 drug metabolism/transport genes. Mid-dosing interval efavirenz concentrations at steady-state were obtained ≥8 h but <19 h post-dose. Linear regression was used to test for associations between polymorphisms and log-transformed efavirenz concentrations.
RESULTS - Increased efavirenz concentrations were associated with CYP2A6 -48T→G in all subjects (P = 3.8 × 10(-4)) and in Black subjects (P = 0.027) and White subjects (P = 0.0011) analysed separately; and with UGT2B7 735 G/G homozygosity in all subjects (P = 0.006) and in Black subjects (P = 0.046) and White subjects (P = 0.062) analysed separately. In a multivariable model, CYP2A6 -48T→G and UGT2B7 735 G/G homozygosity remained significant (P < 0.05 for each). No additional polymorphisms or copy number variants were significantly associated with efavirenz concentrations.
CONCLUSIONS - Among individuals with a CYP2B6 slow metabolizer genotype, CYP2A6 and possibly UGT2B7 polymorphisms contribute to even higher efavirenz concentrations.
© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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19 MeSH Terms