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Portland, OR, United States

Hurlin P.J.,Shriners Hospitals for Children Portland | Hurlin P.J.,Oregon Health And Science University
Cold Spring Harbor Perspectives in Medicine | Year: 2013

The study of MYC has led to pivotal discoveries in cancer biology, induced pluripotency, and transcriptional regulation. In this review, continuing advances in our understanding of the function of MYC as a transcription factor and how its transcriptional activity controls normal vertebrate development and contributes to developmental disorders is discussed. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Link J.M.,Shriners Hospitals for Children Portland | Hurlin P.J.,Shriners Hospitals for Children Portland
Biochimica et biophysica acta | Year: 2015

The MYC family of proteins plays essential roles in embryonic development and in oncogenesis. Efforts over the past 30 years to define the transcriptional activities of MYC and how MYC functions to promote proliferation have produced evolving models of MYC function. One picture that has emerged of MYC and its partner protein MAX is of a transcription factor complex with a seemingly unique ability to stimulate the transcription of genes that are epigenetically poised for transcription and to amplify the transcription of actively transcribed genes. During lymphocyte activation, MYC is upregulated and stimulates a pro-proliferative program in part through the upregulation of a wide variety of metabolic effector genes that facilitate cell growth and cell cycle progression. MYC upregulation simultaneously sensitizes cells to apoptosis and activated lymphocytes and lymphoma cells have pro-survival attributes that allow MYC-driven proliferation to prevail. For example, the MAX-interacting protein MNT is upregulated in activated lymphocytes and was found to protect lymphocytes from MYC-dependent apoptosis. Here we review the activities of MYC, MNT and other MAX interacting proteins in the setting of T and B cell activation and oncogenesis. This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology. Copyright © 2014 Elsevier B.V. All rights reserved. Source


Heberer K.,University of California at Los Angeles | Fowler E.,University of California at Los Angeles | Staudt L.,University of California at Los Angeles | Sienko S.,Shriners Hospitals for Children Portland | And 6 more authors.
Gait and Posture | Year: 2016

Duchenne muscular dystrophy (DMD) is an X-linked genetic neuromuscular disorder characterized by progressive proximal to distal muscle weakness. The success of randomized clinical trials for novel therapeutics depends on outcome measurements that are sensitive to change. As the development of motor skills may lead to functional improvements in young boys with DMD, their inclusion may potentially confound clinical trials. Three-dimensional gait analysis is an under-utilized approach that can quantify joint moments and powers, which reflect functional muscle strength. In this study, gait kinetics, kinematics, spatial-temporal parameters, and timed functional tests were quantified over a one-year period for 21 boys between 4 and 8 years old who were enrolled in a multisite natural history study. At baseline, hip moments and powers were inadequate. Between the two visits, 12 boys began a corticosteroid regimen (mean duration 10.8 ± 2.4 months) while 9 boys remained steroid-naïve. Significant between-group differences favoring steroid use were found for primary kinetic outcomes (peak hip extensor moments (p = .007), duration of hip extensor moments (p = .007), peak hip power generation (p = .028)), and spatial-temporal parameters (walking speed (p = .016) and cadence (p = .021)). Significant between-group differences were not found for kinematics or timed functional tests with the exception of the 10 m walk test (p = .03), which improves in typically developing children within this age range. These results indicate that hip joint kinetics can be used to identify weakness in young boys with DMD and are sensitive to corticosteroid intervention. Inclusion of gait analysis may enhance detection of a treatment effect in clinical trials particularly for young boys with more preserved muscle function. © 2016 Elsevier B.V. Source


Zhou Z.-Q.,Shriners Hospitals for Children Portland | Shung C.-Y.,Shriners Hospitals for Children Portland | Shung C.-Y.,Oregon Health And Science University | Ota S.,Shriners Hospitals for Children Portland | And 4 more authors.
PLoS ONE | Year: 2011

Background: During limb development, chondrocytes and osteoblasts emerge from condensations of limb bud mesenchyme. These cells then proliferate and differentiate in separate but adjacent compartments and function cooperatively to promote bone growth through the process of endochondral ossification. While many aspects of limb skeletal formation are understood, little is known about the mechanisms that link the development of undifferentiated limb bud mesenchyme with formation of the precartilaginous condensation and subsequent proliferative expansion of chondrocyte and osteoblast lineages. The aim of this study was to gain insight into these processes by examining the roles of c-Myc and N-Myc in morphogenesis of the limb skeleton. Methodology/Principal Findings: To investigate c-Myc function in skeletal development, we characterized mice in which floxed c-Myc alleles were deleted in undifferentiated limb bud mesenchyme with Prx1-Cre, in chondro-osteoprogenitors with Sox9-Cre and in osteoblasts with Osx1-Cre. We show that c-Myc promotes the proliferative expansion of both chondrocytes and osteoblasts and as a consequence controls the process of endochondral growth and ossification and determines bone size. The control of proliferation by c-Myc was related to its effects on global gene transcription, as phosphorylation of the C-Terminal Domain (pCTD) of RNA Polymerase II, a marker of general transcription initiation, was tightly coupled to cell proliferation of growth plate chondrocytes where c-Myc is expressed and severely downregulated in the absence of c-Myc. Finally, we show that combined deletion of N-Myc and c-Myc in early limb bud mesenchyme gives rise to a severely hypoplastic limb skeleton that exhibits features characteristic of individual c-Myc and N-Myc mutants. Conclusions/Significance: Our results show that N-Myc and c-Myc act sequentially during limb development to coordinate the expansion of key progenitor populations responsible for forming the limb skeleton. © 2011 Zhou et al. Source


Shung C.-Y.,Shriners Hospitals for Children Portland | Shung C.-Y.,Oregon Health And Science University | Ota S.,Shriners Hospitals for Children Portland | Zhou Z.-Q.,Shriners Hospitals for Children Portland | And 3 more authors.
Human Molecular Genetics | Year: 2012

Mutations in fibroblast growth factor (FGF) receptors are responsible for a variety of skeletal birth defects, but the underlying mechanisms responsible remain unclear. Using a mouse model of thanatophoric dysplasia type II in which FGFR3K650E expression was directed to the appendicular skeleton, we show that the mutant receptor caused a block in chondrocyte differentiation specifically at the prehypertrophic stage. The differentiation block led to a severe reduction in hypertrophic chondrocytes that normally produce vascular endothelial growth factor, which in turn was associated with poor vascularization of primary ossification centers and disrupted endochondral ossification. We show that the differentiation block and defects in joint formation are associated with persistent expression of the chondrogenic factor Sox9 and down-regulation of β-catenin levels and activity in growth plate chondrocytes. Consistent with these in vivo results, FGFR3K650E expression was found to increase Sox9 and decrease β-catenin levels and transcriptional activity in cultured mesenchymal cells. Coexpression of Fgfr3K650E and Sox9 in cells resulted in very high levels of Sox9 and cooperative suppression of β-catenin-dependent transcription. Fgfr3K650E had opposing effects on Sox9 and β-catenin protein stability with it promoting Sox9 stabilization and β-catenin degradation. Since both Sox9 overexpression and β-catenin deletion independently blocks hypertrophic differentiation of chondrocytes and cause chondrodysplasias similar to those caused by mutations in FGFR3, our results suggest that dysregulation of Sox9 and β-catenin levels and activity in growth plate chondrocytes is an important underlying mechanism in skeletal diseases caused by mutations in FGFR3. © The Author 2012. Published by Oxford University Press. All rights reserved. Source

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