The many lives of Myc in the pancreatic β-cell

Abstract

Diabetes results from insufficient numbers of functional pancreatic β-cells. Thus, increasing the number of available functional β-cells ex vivo for transplantation, or regenerating them in situ in diabetic patients, is a major focus of diabetes research. The transcription factor, Myc, discovered decades ago lies at the nexus of most, if not all, known proliferative pathways. Based on this, many studies in the 1990s and early 2000s explored the potential of harnessing Myc expression to expand β-cells for diabetes treatment. Nearly all these studies in β-cells used pathophysiological or supraphysiological levels of Myc and reported enhanced β-cell death, dedifferentiation, or the formation of insulinomas if cooverexpressed with Bcl-xL, an inhibitor of apoptosis. This obviously reduced the enthusiasm for Myc as a therapeutic target for β-cell regeneration. However, recent studies indicate that "gentle" induction of Myc expression enhances β-cell replication without induction of cell death or loss of insulin secretion, suggesting that appropriate levels of Myc could have therapeutic potential for β-cell regeneration. Furthermore, although it has been known for decades that Myc is induced by glucose in β-cells, very little is known about how this essential anabolic transcription factor perceives and responds to nutrients and increased insulin demand in vivo. Here we summarize the previous and recent knowledge of Myc in the β-cell, its potential for β-cell regeneration, and its physiological importance for neonatal and adaptive β-cell expansion.

Keywords: DNA methylation; Myc; adaptation; aging; diabetes; glucose; pancreatic β-cell; proliferation.

Figure 1

Strategies to increase beta cell mass in diabetes. Diabetes occurs when there is a deficiency in functional β-cell mass. β-cell regeneration could be achieved by increasing β-cell replication using Myc-based β-cell-targeted agents. Alternatively, these Myc-based agents could be used to expand β-cells ex vivo for transplantation.

Figure 2

Bell-shaped curve for Myc in β-cells under metabolic stress. Most of what is known about Myc in β-cells is from either supraphysiologic or pathophysiologic concentrations of Myc, resulting in glucotoxicity or apoptosis (shaded). By contrast, little is known about Myc in its native context including whether Myc is necessary for normal adaptive proliferation, mitochondrial activity, and glucose-stimulated insulin secretion (GSIS, unshaded). All these points are examined in this review.

Figure 3

Functions and structure of Myc. A, Myc regulates multiple biological actions essential for the expansion, survival, and normal function of the cell including cell cycle progression and proliferation, cell apoptosis, cell differentiation, cell metabolism, protein synthesis, and mitochondrial biogenesis and function. B, the structure of the Myc protein is highly complex and composed of three regions (N-terminal, central, and C-terminal) containing several domains that are essential for transactivation (Myc Box (MB) I and II), transrepression (MBIII), apoptosis (MBIV), nuclear transport (nuclear localization signal NLS), and DNA binding and Max dimerization (basic (b), helix–loop–helix (HLH) and leucine zipper domain (LZ)). The PEST domain is a polypeptide sequence rich in proline (P), glutamic acid (E), serine (S), and threonine (T). Myc gets phosphorylated at Thr58 and Ser62 and that affects its stability.

Figure 4

Signaling pathways that regulate Myc protein levels in β-cells in basal conditions and in situations of hyperglycemia and increased insulin demand. Signaling pathways depicted here have been inferred from studies in references 33, 74–84 and, 100. Dashed arrows indicate potential pathways. Glucose transporter 2 (Glut2) facilitates glucose movement across the cell membrane. Glycogen synthase kinase 3 (GSK3) phosphorylates Myc on Thr58. In basal conditions (euglycemia), the phosphatase PP2A is not repressed by mTORC1, which leads to Ser62-Myc dephosphorylation, decreased Myc stability, and degradation in β-cells. In acute hyperglycemic events and when insulin demand is increased, PI3K is activated leading to conversion of PIP2 to PIP3 (an action that can be reversed by PTEN), which localizes PDK1 close to the plasma membrane where PDK1-mediated activation of PKC ζ occurs. This leads to mTORC1 activation that impairs PP2A activity preserving Myc phosphorylation on Ser62 by ERK1/2 and increasing Myc stability in β-cells. Myc then translocates to the nucleus with its partner Max, binds to E-boxes on promoters of cell cycle genes such as cyclin A2 (Ccna2), cyclin-dependent kinase 1 (Cdk1), cyclin B1 (Ccnb1), cell division cycle protein 20 (Cdc20), and cell division cycle associated 2 (Cdca2), and induces adaptive β-cell proliferation.

Figure 5

Adaptive β-cell proliferation, Myc stability and action, and DNA methylation in young and aged mice under metabolic stress.A and B, methylation of E-boxes in promoters of cell cycle genes in β-cells from young and aged mice fed regular diet (RD) or high-fat diet (HFD). Differential methylation across all CpG dinucleotides of a region spanning a total of about 1 Mbp containing upregulated cell cycle regulatory genes by HFD in islets from young mice. DNA methylation for CpG dinucleotides was averaged in each group and then subtracted as follows: 8-week-old mice fed HFD—8-week-old mice fed RD (black); 1-year-old mice fed HFD—1-year-old mice fed RD (white). Differential methylation in (A) promoters, gene bodies, and not otherwise mapped regions in the target region and (B) in E-boxes of promoters of specific cell cycle genes after 1-week HFD in young and old mice. Adapted from Rosselot et al. Myc is required for adaptive β-cell replication in young mice but is not sufficient in 1-year-old mice fed with a HFD. Diabetes 2019; 68: 1934–1949. Copyright 2019 by the American Diabetes Association. C, summary of the effects of diet and age on Myc stability and action and β-cell proliferation. β-cells in young mice fed a RD (upper left) display low levels of Myc and low β-cell proliferation rates. β-cells in aged mice fed a RD (upper right) display very low levels of Myc and β-cell proliferation is almost absent. After HFD feeding, β-cells in young mice (lower left) display increased Myc stability leading to high levels of Myc expression, which is required for cell cycle gene expression and adaptive β-cell proliferation and function. β-cells in aged mice fed a HFD (lower right) display increased Myc stability leading to high levels of Myc expression, but compromised binding to cell cycle gene promoters due to the absence of HFD-induced DNA demethylation. The end result is that adaptive β-cell proliferation is impaired in aged mice.