Spelling suggestions: "subject:"stat1"" "subject:"atat1""
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The crosstalk between ITAM-associated receptors and Jak-STAT signaling pathways /Park-Min, Kyung-Hyun. January 2007 (has links)
Thesis (Ph. D.)--Cornell University, January, 2007. / Vita. Includes bibliographical references (leaves 92-106).
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Regulation of dendritic cell and monocyte migration by interferons /Hu, Yang. January 2006 (has links)
Thesis (Ph. D.)--Cornell University, August, 2006. / Vita. Includes bibliographical references (leaves 116-143).
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Odchylky v buněčné signalizaci u primárních imunodeficitů / Cell signaling aberrations in primary immunodeficienciesFejtková, Martina January 2018 (has links)
Primary immunodeficiencies (PID) are genetic disorders characterized by increased susceptibility to infections and various degrees of immune dysregulation. With the expansion of massive parallel sequencing, an increasing number of defects in immune-related genes is being identified in PID. However, the biological impact of the found mutations is often unknown. It is necessary to devise methods to clarify their causality for disease development, which may also aid therapeutic decisions. One of the novel discoveries are gain-of-function mutations in STAT1 gene, resulting in chronic mucocutaneous candidiasis. Candidiasis may be ameliorated with antimycotics or with targeted JAK-STAT inhibitor, ruxolitinib. For our patient with a novel mutation in STAT1, we developed a simple test for the detection of phospho-STAT molecules in peripheral blood lymphocytes. The test confirmed the gain-of-function character of the identified mutation and was used to monitor ruxolitinib treatment efficacy. In the second patient, who presented with lymphadenopathy and immunodeficiency, the as yet undescribed mutation in CASP8 was found. We proved its loss-of-function property expressed as reduced caspase-8 and caspase-3 cleavage, impaired cellular apoptosis, and decreased NFB-related signaling. The third patient who...
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Impact of Toxoplasma gondii on STAT1 activity and epigenetic regulation during IFN-γ signaling of its host cellNast, Roswitha 27 June 2018 (has links)
No description available.
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Phosphorylation of STAT1 Serine 727 Enhances Platinum Resistance in Uterine Serous Carcinoma / 子宮体部漿液性癌において、STAT1のセリン727リン酸化はプラチナ抵抗性に関わるZeng, Xiang 25 November 2019 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22117号 / 医博第4530号 / 新制||医||1039(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 松原 和夫, 教授 滝田 順子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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The Role of Signal Transducer and Activator of Transcription 1 (STAT1) and 3 (STAT3) in Primary and Metastatic Breast CancerRemah Ali (8086364) 05 December 2019 (has links)
<p>Breast cancer is the most frequently diagnosed malignancy and the second
most lethal cancer in women. Metastasis in breast cancer is invariably responsible for patient death
and is comprised of
many steps, of which proliferation in vital organs is responsible for morbidity
and mortality due to vital organ failure. Patients with the metastatic disease
are limited to chemotherapy, which non-specifically targets proliferating
cells. Despite it being initially effective, chemotherapy is associated with high
toxicity and many patients develop resistance. Thus, there is an urgent need to
characterize the biology of metastatic breast cancer to develop targeted
therapies for the late-stage disease.</p>
<p>EGFR is a member of the ErbB family of receptor tyrosine kinases, which
have particular relevance in breast tumorigenesis. Clinical studies show that
high expression levels of EGFR in the primary mammary tumors correlate with
poor prognosis and decreased survival of breast cancer patients due to
metastasis. Patient data is supported by experimental and pre-clinical studies,
which describe various signaling pathways that mediate the oncogenic effects of
EGFR, such as the MAPK, STAT3, and PI3K pathways. Despite these well-documented
roles of EGFR, clinical trials evaluating EGFR inhibitors (EGFRi) in metastatic
breast cancer have been unanimously unsuccessful in improving patient
prognosis, and the mechanisms that contribute to this intrinsic resistance are
unknown.</p>
<p>To characterize the signaling events that govern EGFR behavior in
metastatic breast cancer resistant to EGFRi, we utilized multiple pre-clinical
breast cancer progression series and patient-derived cells that display the intrinsic resistance phenomenon.
In these models, EGFR functions as a pro-apoptotic molecule whose
ligand-mediated activation results in growth inhibition and/or apoptosis of
metastatic breast cancer cells. Here we show that in the later stages of metastasis, increased nuclear translocation
of EGFR leads to increased physical access to STAT1 and STAT3 molecules
residing in the nucleus. Indeed, an EGFR mutant that is defective in
endocytosis is unable to elicit STAT1/3 phosphorylation. Additionally, specific
inhibition of nuclear EGFR function using the EGFR kinase inhibitor gefitinib
linked to a nuclear localization signal (NLS-gefitinib) prevents EGF-induced
STAT1/3 phosphorylation. Altogether, these findings implicate nuclear
localization of EGFR in downstream STAT1/3 signaling in metastatic breast
cancer.</p>
<p>Subsequently, we examined the involvement of nuclearly-activated STAT1/3
signaling in the apoptotic function of EGFR. NLS-gefitinib treatment or
genetic/pharmacologic inhibition of STAT1/3 efficiently blocks EGF-induced
apoptosis in metastatic breast cancer cells resistant to EGFRi. These findings were utilized
therapeutically by activating EGFR with EGF treatment while simultaneously
blocking the downstream proliferative MAPK:ERK1/2 pathway using the MEK1/2
inhibitor trametinib. EGF + trametinib combination preserved STAT1 signaling
while effectively blocking the MAPK pathway, thus potentiating EGF-mediated
apoptosis in metastatic breast cancer cells. Importantly, combined
administration of trametinib and EGF resulted in STAT1-mediated apoptosis of
primary mammary tumor cells, which respond to EGF in a proliferative fashion.
These data provide a novel approach of targeting metastatic breast cancer by
biasing EGFR signaling towards nuclear activation of STAT1/3 signaling
resulting in apoptosis.</p>
Our studies herein also
examined the role of STAT3 in primary mammary tumor cells overexpressing EGFR.
Depletion of STAT3 expression normalized the transformed phenotype of these
cells <i>in vitro</i> and resulted in
smaller mammary tumors <i>in vivo</i>. These
results implicate STAT3 in EGFR-driven breast tumorigenesis localized to the
mammary tissues. Further, systemic dissemination of breast cancer is associated
with activation of the JAK1/2:STAT3 signaling axis. Despite the involvement of
STAT3 in EGFR-mediated oncogenesis in the primary tumor setting, targeting
JAK1/2:STAT signaling with the JAK1/2 inhibitor ruxolitinib proved ineffective
in inhibiting the growth and invasion of metastatic cells derived from these
primary tumors. These results are in agreement with the role of STAT1/3 in
driving the pro-apoptotic function of EGFR in metastatic breast cancer cells.
Altogether, these investigations provide a plausible explanation for the
inability of JAK1/2 inhibitors to effectively target metastatic breast cancer
in clinical and experimental investigations. Further, these findings indicate
that the development of therapeutics or molecular tools that efficiently
activate STAT1/3 signaling in metastatic breast cancer may represent an
important concept for eradicating tumors resistant to targeted therapies.
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Novel Insights into Dedifferentiated Liposarcoma Pathogenesis: Evaluating the Tumor-Promoting Role of IL6/GP130 Signaling via MDM2 UpregulationZewdu, Abeba 03 December 2018 (has links)
No description available.
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Odchylky v buněčné signalizaci u primárních imunodeficitů / Cell signaling aberrations in primary immunodeficienciesFejtková, Martina January 2018 (has links)
Primary immunodeficiencies (PID) are genetic disorders characterized by increased susceptibility to infections and various degrees of immune dysregulation. With the expansion of massive parallel sequencing, an increasing number of defects in immune-related genes is being identified in PID. However, the biological impact of the found mutations is often unknown. It is necessary to devise methods to clarify their causality for disease development, which may also aid therapeutic decisions. One of the novel discoveries are gain-of-function mutations in STAT1 gene, resulting in chronic mucocutaneous candidiasis. Candidiasis may be ameliorated with antimycotics or with targeted JAK-STAT inhibitor, ruxolitinib. For our patient with a novel mutation in STAT1, we developed a simple test for the detection of phospho-STAT molecules in peripheral blood lymphocytes. The test confirmed the gain-of-function character of the identified mutation and was used to monitor ruxolitinib treatment efficacy. In the second patient, who presented with lymphadenopathy and immunodeficiency, the as yet undescribed mutation in CASP8 was found. We proved its loss-of-function property expressed as reduced caspase-8 and caspase-3 cleavage, impaired cellular apoptosis, and decreased NFB-related signaling. The third patient who...
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Regulation of STAT6, STAT3 and STAT1 by the Cytoplasmic Tail of Polycystin-1, the Protein Affected in Polycystic Kidney DiseaseShivakumar, Vasanth 01 May 2007 (has links)
No description available.
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Identifying Novel Disease-associated Variants and Understanding the Role of the STAT1-STAT4 Locus in SLEPatel, Zubin 15 December 2017 (has links)
No description available.
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