Mist1 Regulates Pancreatic Acinar Cell Proliferation Through p21CIP1/WAF1

Jia, Di; Sun, Yan; Konieczny, Stephen F.

doi:10.1053/j.gastro.2008.07.026

Cited by 52 publications

(55 citation statements)

References 42 publications

(47 reference statements)

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“…Because MIST1 is restricted to professional secretory cells (e.g., acinar cells), we asked if nonsecretory cells could similarly induce Mist1 expression upon ER stress. For these studies, we utilized a number of human pancreatic ductal cell lines that normally do not express Mist1 (14,20,25,40,41). In all cases, treatment of cells with thapsigargin led to induction of Xbp1s and Mist1 transcripts ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Secretory cells utilize transcription factor networks to alter their cytoskeletal arrangement, polarity, membrane protein composition, and organelle makeup to support the proper generation, storage, and release of protein products (8). Recently, the basic helix-loop-helix (bHLH) transcription factor MIST1 (encoded by Bhlha15) has emerged as a potent regulator of a wide variety of secretory cell functions and responses to stress (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Secretory cells lacking MIST1 exhibit structural and functional defects, including altered cytoskeletal organization, a change in cell polarity, and improper cell-to-cell communication (12,17,(19)(20)(21).…”

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confidence: 99%

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MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

Hess

Strelau

Karki

et al. 2016

Molecular and Cellular Biology

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Transcriptional networks that govern secretory cell specialization, including instructing cells to develop a unique cytoarchitecture, amass extensive protein synthesis machinery, and be embodied to respond to endoplasmic reticulum (ER) stress, remain largely uncharacterized. In this study, we discovered that the secretory cell transcription factor MIST1 (Bhlha15), previously shown to be essential for cytoskeletal organization and secretory activity, also functions as a potent ER stress-inducible transcriptional regulator. Genome-wide DNA binding studies, coupled with genetic mouse models, revealed MIST1 gene targets that function along the entire breadth of the protein synthesis, processing, transport, and exocytosis networks. Additionally, key MIST1 targets are essential for alleviating ER stress in these highly specialized cells. Indeed, MIST1 functions as a coregulator of the unfolded protein response (UPR) master transcription factor XBP1 for a portion of target genes that contain adjacent MIST1 and XBP1 binding sites. Interestingly, Mist1 gene expression is induced during ER stress by XBP1, but as ER stress subsides, MIST1 serves as a feedback inhibitor, directly binding the Xbp1 promoter and repressing Xbp1 transcript production. Together, our findings provide a new paradigm for XBP1-dependent UPR regulation and position MIST1 as a potential biotherapeutic for numerous human diseases.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

Hess

Strelau

Karki

et al. 2016

Molecular and Cellular Biology

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“…Ultimately, the mature pancreas has acinar-to-ductal metaplasia and acinar autodigestion. Recently, Jia et al (2008) suggested that Mist1 controls acinar proliferation by increasing the level of the negative cell cycle regulator p21 CIP1/WAF1 . Deleting Mist1 in mature acini causes increased proliferation via reduced p21 CIP1/WAF1 expression.…”

Section: Acinar Formationmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

524

594

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Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature b-cells. Developmental Dynamics 240:530-565,

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“…MIST1 expression is a feature of all serous exocrine cells (Lemercier et al, 1997;Pin et al, 2000). Recent work has begun to identify the molecular targets that it scales up to establish a high-capacity polarized secretory apparatus (Capoccia et al, 2013;Direnzo et al, 2012;Garside et al, 2010;Jia et al, 2008;Johnson et al, 2004;Pin et al, 2001;Rukstalis et al, 2003;Tian et al, 2010). For example, RAB3D has been identified as a target in both pancreatic and gastric exocrine cells (Johnson et al, 2004;Tian et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

RAB26 coordinates lysosome traffic and mitochondrial localization

Jin

Mills

2014

Journal of Cell Science

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As they mature, professional secretory cells like pancreatic acinar and gastric chief cells induce the transcription factor MIST1 (also known as BHLHA15) to substantially scale up production of large secretory granules in a process that involves expansion of apical cytoplasm and redistribution of lysosomes and mitochondria. How a scaling factor like MIST1 rearranges cellular architecture simply by regulating expression levels of its transcriptional targets is unknown. RAB26 is a MIST1 target whose role in MIST1-mediated secretory cell maturation is also unknown. Here, we confirm that RAB26 expression, unlike most Rabs which are ubiquitously expressed, is tissue specific and largely confined to MIST1-expressing secretory tissues. Surprisingly, functional studies showed that RAB26 predominantly associated with LAMP1/cathepsin D lysosomes and not directly with secretory granules. Moreover, increasing RAB26 expression -by inducing differentiation of zymogensecreting cells or by direct transfection -caused lysosomes to coalesce in a central, perinuclear region. Lysosome clustering in turn caused redistribution of mitochondria into distinct subcellular neighborhoods. The data elucidate a novel function for RAB26 and suggest a mechanism for how cells could increase transcription of key effectors to reorganize subcellular compartments during differentiation.

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Mist1 Regulates Pancreatic Acinar Cell Proliferation Through p21CIP1/WAF1

Abstract: Background & Aims-Mist1 is a basic helix-loop-helix (bHLH) transcription factor that is important to the proper development of the exocrine pancreas. The aim of this study was to investigate the role of Mist1 in modulating acinar cell proliferation.

Cited by 52 publications

References 42 publications

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

Pancreas organogenesis: From bud to plexus to gland

RAB26 coordinates lysosome traffic and mitochondrial localization

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