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Related Experiment Video

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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9

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Published on: August 28, 2018

Pax6 directly down-regulates Pcsk1n expression thereby regulating PC1/3 dependent proinsulin processing.

Ting Liu¹, Yanxia Zhao, Na Tang

¹Peking University Stem Cell Research Center, Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

|October 12, 2012

Summary

Pax6 mutations impair glucose metabolism by affecting proinsulin processing. Pax6 directly reduces Pcsk1n expression, enhancing PC1/3 activity and improving insulin production.

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Area of Science:

Endocrinology
Molecular Biology
Genetics

Background:

Paired box6 (Pax6) mutations are linked to abnormal glucose metabolism.
Pax6 deficiency impairs proinsulin processing by down-regulating prohormone convertase 1/3 (Pcsk1).
The activity of PC1/3, crucial for its function, is as important as its expression levels.

Purpose of the Study:

To investigate how Pax6 mutations affect PC1/3 activity.
To elucidate the molecular mechanism linking Pax6, PC1/3 activity, and proinsulin processing.

Main Methods:

Quantitative RT-PCR and western blot to assess gene and protein expression.
Enzyme activity assays to measure PC1/3 function.
Luciferase reporter assays, chromatin immunoprecipitation, and electrophoretic mobility shift assays to study gene regulation.
RNA interference (RNAi) to modulate gene expression.

Main Results:

Pax6 R266Stop mutation compromised PC1/3 C-terminal cleavage and activity.
Pax6 deficiency elevated Pcsk1n (proSAAS) expression, a PC1/3 inhibitor.
Pax6 directly binds to the Pcsk1n promoter, down-regulating its expression.
Pax6 knockdown inhibited proinsulin processing, an effect rescued by proSAAS knockdown.

Conclusions:

Pax6 directly down-regulates Pcsk1n (proSAAS) expression.
Reduced Pcsk1n enhances PC1/3 activity, facilitating proinsulin processing.
ProSAAS is a novel Pax6 target involved in glucose metabolism regulation.
This study reveals a molecular mechanism for Pax6 deficiency-induced diabetes.