The Impact of Two Truncated STAT5B on Signaling Pathway and Human Growth

The Impact of Two Truncated STAT5B on Signaling Pathway and Human Growth

Bibliographic Details
Main Author: Gao, Wen
Language:English
Published: University of Cincinnati / OhioLINK 2021
Subjects:
Immunology
STAT5B mutations
Growth hormone insensitivity
IL6 insensitivity
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613751460162334
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin16137514601623342021-08-03T07:16:50Z The Impact of Two Truncated STAT5B on Signaling Pathway and Human Growth Gao, Wen Immunology STAT5B mutations Growth hormone insensitivity IL6 insensitivity The signal transducer and activator of transcription STAT5B, is involved in signal transduction for many cytokines and growth factors, including growth hormone (GH). STAT5B deficiency due to inactivating STAT5B mutations result in human growth and immune impairments. Two homozygous frameshift mutations of STAT5B (c.1102insC and c.1453delG) which led to the truncated proteins were identified in patients with short stature, delayed bone ages and growth hormone insensitivity(GHI) but lack the severe immune dysfunction and pulmonary insufficiencies normally associated with STAT5B deficiency. To understand the properties of the two STAT5B mutations and the mechanisms responsible for GHI and lack of severe immune dysfunction, mutation regeneration and HEK reconstitution analysis were performed. Results showed that the mutant STAT5B could be stably expressed in reconstitution system. Due to the loss of main tyrosine phosphorylation site Y699,mutant STAT5B failed to be activate upon GH stimulation. Cytoplasmic aggresomes were observed in transfected cells with the truncated STAT5B c.1453delG. GHI was, therefore, a result of disruption of STAT5B signaling downstream from the GH receptor.For c.1102insC STAT5B carrying primary fibroblasts, the cells exhibit poor response to pro-inflammatory IL6, as measured by significantly decreased phosphorylation of the transcription factor STAT3. Unlike other STAT5B deficient patients who had severe immune diseases or pulmonary problems, patient carrying STAT5Bc.1102insC did not have such problems. Therefore, the resistance to IL6 found in the patient may suggest a new IL6-involved mechanism compensating for a severe STAT5B deficiency state(immunodeficiency and chronic pulmonary diseases)Studying causes of poor IL6 insensitivity in STAT5Bc.1102insC cells might help us to further understand this unidentified mechanism. In STAT5Bc.1102insC fibroblasts, we show that abrogated IL6 signaling was not due to defects of the various components involved in the IL6 signaling pathway, including mIL6R, gp130 and STAT3. Interestingly, in reconstitution studies, results supported STAT5B-STAT3 heterodimers playing a role in modulating IL6 signaling, including enhancing nuclear localization of STAT3. STAT5Bc.1102insC, in contrast, interacted poorly with STAT3 with reduced STAT3 nuclear translocation observed. In summary,STAT5B could facilitate STAT3 nuclear translocation in IL6 signaling via STAT5B-STAT3 heterodimer, while STAT5Bc.1102insC interfered with STAT3 nuclear translocation in the cells upon IL6 stimulation. 2021-04-01 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613751460162334 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613751460162334 restricted--full text unavailable until 2022-04-01 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Immunology
STAT5B mutations
Growth hormone insensitivity
IL6 insensitivity
spellingShingle Immunology
STAT5B mutations
Growth hormone insensitivity
IL6 insensitivity
Gao, Wen
The Impact of Two Truncated STAT5B on Signaling Pathway and Human Growth
author Gao, Wen
author_facet Gao, Wen
author_sort Gao, Wen
title The Impact of Two Truncated STAT5B on Signaling Pathway and Human Growth
title_short The Impact of Two Truncated STAT5B on Signaling Pathway and Human Growth
title_full The Impact of Two Truncated STAT5B on Signaling Pathway and Human Growth
title_fullStr The Impact of Two Truncated STAT5B on Signaling Pathway and Human Growth
title_full_unstemmed The Impact of Two Truncated STAT5B on Signaling Pathway and Human Growth
title_sort impact of two truncated stat5b on signaling pathway and human growth
publisher University of Cincinnati / OhioLINK
publishDate 2021
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613751460162334
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