Biology subjects

Guan, B.-J.

Publications and source records attributed to Guan, B.-J..

3 recordsLinked to original sources

bioRxiv2021

Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

Pancreatic {beta}-cells undergo high levels of endoplasmic reticulum (ER) stress due to their role in insulin secretion. Hence, they require sustainable and efficient adaptive stress responses to cope with the stress. Whether duration and episodes of chronic ER stress directly compromises {beta}-cell identity is largely unknown. We show that under reversible, chronic ER stress, {beta}-cells undergo a distinct transcriptional and translational reprogramming. During reprogramming, expression of master regulators of {beta}-cell function and identity and proinsulin processing is impaired. Upon recovery from stress, {beta}-cells regain their identity, highlighting a high-degree of adaptive {beta}-cell plasticity. Remarkably, when stress episodes exceed a certain threshold, {beta}-cell identity is gradually lost. Single cell RNA-seq analysis of islets from type 1 diabetes (T1D) patients, identifies the severe deregulation of the chronic stress-adaptation program, and reveals novel biomarkers for progression of T1D. Our results suggest {beta}-cell adaptive exhaustion ({beta}EAR) is a significant component of the pathogenesis of T1D.

systems biology↗

bioRxiv2020

Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress

Mammalian cells have to adapt to environmental challenges that range from mild to severe stress. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe stress conditions, cells induce a transient hibernation-like mechanism that anticipates recovery. We demonstrate that this Adaptive Pausing Response (APR) is a coordinated cellular response that limits ATP supply and consumption though mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery from severe stress. We further show that recovery from severe stress involves adaptive ISR (Integrated Stress Response) signaling that in turn permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress through the APR, a mechanism that preserves vital elements of cellular function under harsh environmental conditions.

molecular biology↗

bioRxiv2019

Translational control of breast cancer plasticity

Plasticity of neoplasia, whereby cancer cells attain stem-cell-like properties, is required for disease progression and represents a major therapeutic challenge. We report that in breast cancer cells NANOG, SNAIL and NODAL transcripts manifest multiple isoforms characterized by different 5 Untranslated Regions (5UTRs), whereby translation of a subset of these isoforms is stimulated under hypoxia. This leads to accumulation of corresponding proteins which induce plasticity and \"fate-switching\" toward stem-cell like phenotypes. Surprisingly, we observed that mTOR inhibitors and chemotherapeutics induce translational activation of a subset of NANOG, SNAIL and NODAL mRNA isoforms akin to hypoxia, engendering stem cell-like phenotypes. Strikingly, these effects can be overcome with drugs that antagonize translational reprogramming caused by eIF2 phosphorylation (e.g. ISRIB). Collectively, our findings unravel a hitherto unappreciated mechanism of induction of plasticity of breast cancer cells, and provide a molecular basis for therapeutic strategies aimed at overcoming drug resistance and abrogating metastasis.

cancer biology↗