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Phosphatidylinositol 3-kinase is a negative regulator of cellular differentiation
A Ptasznik1, G M Beattie, M I Mally
1The Whittier Institute for Diabetes and Endocrinology, Department of Pediatrics, University of California at San Diego, School of Medicine, La Jolla, California 92037, USA.
Abstract:
Phosphatidylinositol 3-kinase (PI3K) has been shown to be an important mediator of intracellular signal transduction in mammalian cells. We show here, for the first time, that the blockade of PI3K activity in human fetal undifferentiated cells induced morphological and functional endocrine differentiation. This was associated with an increase in mRNA levels of insulin, glucagon, and somatostatin, as well as an increase in the insulin protein content and secretion in response to secretagogues. Blockade of PI3K also increased the proportion of pluripotent precursor cells coexpressing multiple hormones and the total number of terminally differentiated cells originating from these precursor cells. We examined whether any of the recently described modulators of endocrine differentiation could participate in regulating PI3K activity in fetal islet cells. The activity of PI3K was inversely correlated with the hepatocyte growth factor/scatter factor-induced downregulation or nicotinamideinduced upregulation of islet-specific gene expression, giving support to the role of PI3K, as a negative regulator of endocrine differentiation. In conclusion, our results provide a mechanism for the regulation of hormone-specific gene expression during human fetal neogenesis. They also suggest a novel function for PI3K, as a negative regulator of cellular differentiation.
Insights
Blocking Phosphatidylinositol 3-kinase (PI3K) activity in human fetal cells promotes endocrine differentiation. This pathway negatively regulates hormone-specific gene expression and cellular differentiation during human fetal neogenesis.
Area of Science:
- Cell Biology
- Endocrinology
- Developmental Biology
Background:
- Phosphatidylinositol 3-kinase (PI3K) is a key mediator of intracellular signal transduction in mammalian cells.
- Endocrine differentiation is a complex process crucial for hormone production and regulation.
Purpose of the Study:
- To investigate the role of PI3K in regulating endocrine differentiation in human fetal cells.
- To elucidate the mechanism by which PI3K influences hormone-specific gene expression and cellular differentiation.
Main Methods:
- Blockade of PI3K activity in human fetal undifferentiated cells.
- Analysis of mRNA levels for insulin, glucagon, and somatostatin.
- Measurement of insulin protein content and secretion.
- Assessment of pluripotent precursor cell populations and terminally differentiated cells.
Main Results:
- PI3K blockade induced morphological and functional endocrine differentiation.
- Increased mRNA levels of insulin, glucagon, and somatostatin were observed.
- Enhanced insulin protein content and secretion, along with increased coexpression of multiple hormones in precursor cells.
- PI3K activity was inversely correlated with known modulators of endocrine differentiation, suggesting a negative regulatory role.
Conclusions:
- PI3K acts as a negative regulator of endocrine differentiation in human fetal cells.
- This study provides a novel mechanism for regulating hormone-specific gene expression during human fetal neogenesis.
- PI3K's role as a negative regulator of cellular differentiation is highlighted.