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"Shaw, Patrick"
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C9orf72 nucleotide repeat structures initiate molecular cascades of disease
A hexanucleotide repeat expansion (HRE), (GGGGCC)
n
, in
C9orf72
is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA•DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct
C9orf72
HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.
Structurally polymorphic
C9orf72
hexanucleotide repeats cause an impairment in transcriptional processivity and lead to accumulation of truncated repeat-containing transcripts that bind to specific ribonucleoproteins, such as nucleolin, in a conformation-dependent manner resulting in nucleolar stress and
C9orf72
-linked pathology in amyotrophic lateral sclerosis and frontotemporal dementia.
RNA toxicity in
C9orf72
-linked neuropathology
Repeat expansions — mutations in which extra copies of tandemly repeated DNA sequence are generated — underlie more than 40 genetic diseases, which typically lead to neurological and neuromuscular problems. The
C9orf72
hexanucleotide repeat expansion has been identified as a cause for both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Normal
C9orf72
contains up to 25 repeats, whereas those in afflicted individuals can have thousands. This study suggests that a gain in RNA toxicity underlies
C9orf72
-linked pathology in ALS/FTD. Transcribed
C9orf72
hexanucleotide repeats are shown to bind to specific ribonucleoproteins, such as nucleolin, in a conformation-dependent manner; as a result nucleolin is mislocalized and functionally impaired, leading to nucleolar stress.
Journal Article
The art of music
\"The Art of music is a handsomely illustrated and rich interdisciplinary look at the mutual influence between music and the visual arts across cultures and eras. The book sheds new light on more familiar artists at the intersection of the visual and the musical, such as Wassily Kandinsky and Arnold Schoenberg, and presents new scholarship on less well-known examples in the arts of Asia, Africa, the Americas, and Europe, from antique pottery to contemporary video and sound art. Essays consider key works and themes such as synesthesia and other formal and theoretical crossovers, motifs of musicians, and performative and ritual functions of music, musical instruments, and art. With more than 250 color images illustrating works of art in diverse traditions, The Art of music offers enriching reading for scholars and general audiences alike\"-- Provided by publisher.
Book
STIM1 and STIM2-mediated Ca(2+) influx regulates antitumour immunity by CD8(+) T cells
Store-operated calcium entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels regulates the function of many immune cells. Patients with loss-of-function mutations in the CRAC channel genes ORAI1 or STIM1 are immunodeficient and are prone to develop virus-associated tumours. This and the reported role of Ca(2+) signals in cytotoxic lymphocyte function suggest that SOCE may be critical for tumour immune surveillance. Using conditional knock out mice lacking STIM1 and its homologue STIM2, we find that SOCE in CD8(+) T cells is required to prevent the engraftment of melanoma and colon carcinoma cells and to control tumour growth. SOCE is essential for the cytotoxic function of CTLs both in vivo and in vitro by regulating the degranulation of CTLs, their expression of Fas ligand and production of TNF-α and IFN-γ. Our results emphasize an important role of SOCE in antitumour immunity, which is significant given recent reports arguing in favour of CRAC channel inhibition for cancer therapy.
Journal Article
Phosphoproteomic Profiling Reveals Epstein-Barr Virus Protein Kinase Integration of DNA Damage Response and Mitotic Signaling
Epstein-Barr virus (EBV) is etiologically linked to infectious mononucleosis and several human cancers. EBV encodes a conserved protein kinase BGLF4 that plays a key role in the viral life cycle. To provide new insight into the host proteins regulated by BGLF4, we utilized stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomics to compare site-specific phosphorylation in BGLF4-expressing Akata B cells. Our analysis revealed BGLF4-mediated hyperphosphorylation of 3,046 unique sites corresponding to 1,328 proteins. Frequency analysis of these phosphosites revealed a proline-rich motif signature downstream of BGLF4, indicating a broader substrate recognition for BGLF4 than its cellular ortholog cyclin-dependent kinase 1 (CDK1). Further, motif analysis of the hyperphosphorylated sites revealed enrichment in ATM, ATR and Aurora kinase substrates while functional analyses revealed significant enrichment of pathways related to the DNA damage response (DDR), mitosis and cell cycle. Phosphorylation of proteins associated with the mitotic spindle assembly checkpoint (SAC) indicated checkpoint activation, an event that inactivates the anaphase promoting complex/cyclosome, APC/C. Furthermore, we demonstrated that BGLF4 binds to and directly phosphorylates the key cellular proteins PP1, MPS1 and CDC20 that lie upstream of SAC activation and APC/C inhibition. Consistent with APC/C inactivation, we found that BGLF4 stabilizes the expression of many known APC/C substrates. We also noted hyperphosphorylation of 22 proteins associated the nuclear pore complex, which may contribute to nuclear pore disassembly and SAC activation. A drug that inhibits mitotic checkpoint activation also suppressed the accumulation of extracellular EBV virus. Taken together, our data reveal that, in addition to the DDR, manipulation of mitotic kinase signaling and SAC activation are mechanisms associated with lytic EBV replication. All MS data have been deposited in the ProteomeXchange with identifier PXD002411 (http://proteomecentral.proteomexchange.org/dataset/PXD002411).
Journal Article
Molecular regulation of CRAC channels and their role in lymphocyte function
Calcium (Ca²⁺) influx is required for the activation and function of all cells in the immune system. It is mediated mainly by store-operated Ca²⁺entry (SOCE) through Ca²⁺release-activated Ca²⁺(CRAC) channels located in the plasma membrane. CRAC channels are composed of ORAI proteins that form the channel pore and are activated by stromal interaction molecules (STIM) 1 and 2. Located in the membrane of the endoplasmic reticulum, STIM1 and STIM2 have the dual function of sensing the intraluminal Ca²⁺concentration in the ER and to activate CRAC channels. A decrease in the ER’s Ca²⁺concentration induces STIM multimerization and translocation into puncta close to the plasma membrane where they bind to and activate ORAI channels. Since the identification of ORAI and STIM genes as the principal mediators of CRAC channel function, substantial advances have been achieved in understanding the molecular regulation and physiological role of CRAC channels in cells of the immune system and other organs. In this review, we discuss the mechanisms that regulate CRAC channel function and SOCE, the role of recently identified proteins and mechanisms that modulate the activation of ORAI/STIM proteins and the consequences of CRAC channel dysregulation for lymphocyte function and immunity.
Journal Article
STIM1 and STIM2‐mediated Ca2+ influx regulates antitumour immunity by CD8+ T cells
Store‐operated calcium entry (SOCE) through Ca
2+
release‐activated Ca
2+
(CRAC) channels regulates the function of many immune cells. Patients with loss‐of‐function mutations in the CRAC channel genes
ORAI1
or
STIM1
are immunodeficient and are prone to develop virus‐associated tumours. This and the reported role of Ca
2+
signals in cytotoxic lymphocyte function suggest that SOCE may be critical for tumour immune surveillance. Using conditional knock out mice lacking STIM1 and its homologue STIM2, we find that SOCE in CD8
+
T cells is required to prevent the engraftment of melanoma and colon carcinoma cells and to control tumour growth. SOCE is essential for the cytotoxic function of CTLs both
in vivo
and
in vitro
by regulating the degranulation of CTLs, their expression of Fas ligand and production of TNF‐α and IFN‐γ. Our results emphasize an important role of SOCE in antitumour immunity, which is significant given recent reports arguing in favour of CRAC channel inhibition for cancer therapy.
Graphical Abstract
Cytotoxic lymphocytes are critical for antitumor immunity. Here, store operated calcium entry (SOCE) mediated by STIM1 and ‐2 is shown essential to CD8
+
T cells antitumor immune responses, arguing against the use of drugs inhibiting SOCE.
Journal Article
Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane-treated human breast epithelial cells reveals common expression profiles
Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a potent inhibitor of experimental mammary carcinogenesis and may be an effective, safe chemopreventive agent for use in humans. SFN acts in part on the Keap1/Nrf2 pathway to regulate a battery of cytoprotective genes. In this study, transcriptomic and proteomic changes in the estrogen receptor negative, non-tumorigenic human breast epithelial MCF10A cell line were analyzed following SFN treatment or KEAP1 knockdown with siRNA using microarray and stable isotopic labeling with amino acids in culture (SILAC), respectively. Changes in selected transcripts and proteins were confirmed by PCR and Western blot in MCF10A and MCF12A cells. There was strong correlation between the transcriptomic and proteomic responses in both the SFN treatment (
R
= 0.679,
P
< 0.05) and KEAP1 knockdown (
R
= 0.853,
P
< 0.05) experiments. Common pathways for SFN treatment and KEAP1 knockdown were xenobiotic metabolism and antioxidants, glutathione metabolism, carbohydrate metabolism, and NADH/NADPH regeneration. Moreover, these pathways were most prominent in both the transcriptomic and the proteomic analyses. The aldo–keto reductase family members, AKR1B10, AKR1C1, AKR1C2 and AKR1C3, as well as NQO1 and ALDH3A1, were highly upregulated at both the transcriptomic and the proteomic levels. Collectively, these studies served to identify potential biomarkers that can be used in clinical trials to investigate the initial pharmacodynamic action of SFN in the breast.
Journal Article
The Public Right to Education
Public education is \"the most important function of state and local government\" and yet not a \"fundamental right or liberty.\" This Article engages one of constitutional law's most intractable problems by introducing \"the public right to education\" as a doctrinal pathway to a constitutional right to education process in three steps. First, it identifies that the otherwise right-to-education foreclosing case, San Antonio Independent School District v. Rodriguez, only contemplated education as a fundamental right or liberty interest. Second, by identifying public education as a due process–protected property interest, this Article presents a viable pathway for circumventing Rodriguez. Third, mindful of myriad judicial competency concerns and consistent with the Court's recent call to reimagine a \"twenty-firstcentury\" due process, it reintroduces the \"public right\" to understand how schoolchildren might appeal to substantive due process to protect their rights to state-created interests. This ambitious yet modest approach covers securing schoolchildren's rights to both discrete education tangibles and the integral educational opportunity that the states have assumed the affirmative duty to provide. This approach also has promise for improving individual rights to quality public schooling.
Journal Article
Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells
Abnormal activities of histone lysine demethylases (KDMs) and lysine deacetylases (HDACs) are associated with aberrant gene expression in breast cancer development. However, the precise molecular mechanisms underlying the crosstalk between KDMs and HDACs in chromatin remodeling and regulation of gene transcription are still elusive. In this study, we showed that treatment of human breast cancer cells with inhibitors targeting the zinc cofactor dependent class I/II HDAC, but not NAD
+
dependent class III HDAC, led to significant increase of H3K4me2 which is a specific substrate of histone lysine-specific demethylase 1 (LSD1) and a key chromatin mark promoting transcriptional activation. We also demonstrated that inhibition of LSD1 activity by a pharmacological inhibitor, pargyline, or siRNA resulted in increased acetylation of H3K9 (AcH3K9). However, siRNA knockdown of LSD2, a homolog of LSD1, failed to alter the level of AcH3K9, suggesting that LSD2 activity may not be functionally connected with HDAC activity. Combined treatment with LSD1 and HDAC inhibitors resulted in enhanced levels of H3K4me2 and AcH3K9, and exhibited synergistic growth inhibition of breast cancer cells. Finally, microarray screening identified a unique subset of genes whose expression was significantly changed by combination treatment with inhibitors of LSD1 and HDAC. Our study suggests that LSD1 intimately interacts with histone deacetylases in human breast cancer cells. Inhibition of histone demethylation and deacetylation exhibits cooperation and synergy in regulating gene expression and growth inhibition, and may represent a promising and novel approach for epigenetic therapy of breast cancer.
Journal Article