Exocrine specific expression of Connexin32 is dependent on the basic helix-loop-helix transcription factor Mist1

Rukstalis, J. Michael; Kowalik, Agnes S.; Zhu, Linghui; Lidington, Darcy; Pin, Christopher L.; Konieczny, Stephen F.

doi:10.1242/jcs.00631

Cited by 66 publications

(70 citation statements)

References 50 publications

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“…MIST1 can function as a transcriptional activator or repressor for individual targets (12,23,66), giving it enormous capability to modulate and fine-tune cellular responses. Indeed, the breadth of MIST1's influence throughout the cell has hindered previous attempts to determine why cells lacking MIST1 exhibit a crippled capacity to synthesize and secrete protein products (12,21).…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…However, acini in Mist1 À/À mice do not acquire the typical rosette-like morphology, possibly as a consequence of loss of functional gap junctions that was attributed to reduced connexin-32 levels (Zhu et al, 2004). Mist1-null acini lose apical-basal polarity (Pin et al, 2001) and exocytosis is impaired with intracellularly misdirected zymogen granules (Rukstalis et al, 2003). Ultimately, the mature pancreas has acinar-to-ductal metaplasia and acinar autodigestion.…”

Section: Acinar Formationmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

525

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 is a basic helix-loop-helix transcription factor that is essential for the normal development of serous acinar cells in various secretory glands, including the pancreas and salivary glands (26 -30). Deletion of the Mist1 gene (26,30) or inhibition of Mist1 function (28,29) leads to severe distortion of acinar cellular architecture, including loss of gap junctions and intercellular communication (28,30), disorder of secretory granules (26 -30), and acinar-to-ductal metaplasia (29). Additional changes in Mist1 Ϫ/Ϫ cells include up-regulation of mRNA coding for the cholecystokinin (CCK) receptors and down-regulation of expression of IP 3 R3 (26).…”

Section: Camentioning

confidence: 99%

Aberrant Localization of Intracellular Organelles, Ca2+ Signaling, and Exocytosis in Mist1 Null Mice

Luo

Shin

Wang

et al. 2005

Journal of Biological Chemistry

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Ca2؉ signaling and exocytosis are highly polarized functions of pancreatic acinar cells. ؊/؊ cells. Deletion of Mist1 also led to mislocalization of the Golgi apparatus and markedly reduced digestive enzyme content. The combination of aberrant Ca 2؉ signaling and reduced digestive enzyme content resulted in poor secretion of digestive enzymes. Yet, food consumption and growth of Mist1 ؊/؊ mice were normal for at least 32 weeks. These findings reveal that Mist1 is critical to normal organelle localization in exocrine cells and highlight the critical importance of maintaining cellular architecture and polarized localization of cellular organelles in generating a propagating apical-to-basal Ca 2؉ wave. The studies also reveal the spare capacity of the exocrine pancreas that allows normal growth and development in the face of compromised exocrine pancreatic function.

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Exocrine specific expression of Connexin32 is dependent on the basic helix-loop-helix transcription factor Mist1

Cited by 66 publications

References 50 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

Aberrant Localization of Intracellular Organelles, Ca2+ Signaling, and Exocytosis in Mist1 Null Mice

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