The Ayer Lab studies the transcriptional control of cellular proliferation and how these controls are subverted in human malignancy. We are currently focused on understanding how cells communicate information about their metabolic state to the nucleus to drive adaptive changes in gene expression. Furthermore, we are interested in how these metabolic signals coordinate with the signals that control cell growth, division, and death. We use a wide array of approaches from biochemistry and cell biology to genomics to examine these questions. Our efforts are focused on communication between mitochondria and the nucleus and how these pathways match the availability of glucose with its use in biosynthetic pathways to support anabolic cancer cell growth.
Myc, MondoA, and Metabolism
Myc is a basic region helix-loop-helix leucine zipper (bHLHZip) transcription factor, whose expression is dysregulated in many types of cancer. It functions as a transcriptional activator when dimerized to another bHLHZip protein called Max to drive expression of genes involved in pro-growth pathways. These include biosynthetic pathways such as nucleotide biosynthesis and ribosomal biogenesis. These biosynthetic reactions require carbon skeleton precursors derived primarily from glucose. Myc:Max complexes control the uptake of glucose and its flux into biosynthetic pathways by inducing expression of its membrane-bound transporters and key glycolytic genes. Thus, Myc controls the intracellular availability of key nutrients and their utilization.
Myc functions within a large network of related transcriptional regulators. Over the last 25 years, we have advanced the concept of an “extended” Myc network. The transcriptional activity of Myc:Max complexes is under tight regulatory control: balanced by the Mxd(Mad) family of transcriptional repressors and by a parallel Myc-like transcription factor network that has Max-like protein X (Mlx) at its center. Like Max, Mlx is a small and highly conserved bHLHZip protein with a number of heterodimeric partners. Mlx interacts primarily with the Mondo family of transcription activators, which comprises two bHLHZip proteins, MondoA and ChREBP; our lab discovered MondoA. Mlx can also interact with a subset of the Mad(Mxd) family, but not with Max or any of the Myc family. A number of papers indicate that there is functional crosstalk between Myc:Max and MondoA:Mlx complexes. Exploring the molecular underpinnings of Myc and MondoA crosstalk is one focus of our laboratory.
MondoA Is an Energy Sensor
MondoA:Mlx complexes are interesting in that they localize to the cytoplasm and their nuclear and transcriptional activity is tightly regulated. MondoA:Mlx complexes localize to the outer mitochondrial membrane, suggesting that they sense cellular bioenergetics and/or metabolic state. Supporting this contention, MondoA transcriptional activity is stimulated by glucose 6-phosphate, which is the first intermediate in glycolysis. Once nuclear, MondoA regulates the expression of a gene called Thioredoxin Interacting Protein, which is a potent negative regulator of glucose uptake, to reestablish glucose homeostasis. Our experimental efforts are centered on determining how MondoA senses glucose 6-phosphate, understanding the mechanisms that dictate the subcellular localization of MondoA:Mlx complexes and the molecular pathways regulated by MondoA:Mlx complexes in response to changing mitochondrial function and nutrient state.