John A. Hanover, Ph.D.
Laboratory of Cell and Molecular Biology
Building 8, Room B127
8 Center Drive
Bethesda, MD 20814
Our laboratory focuses on (1) the molecular features of a novel, glycan-dependent, signal transduction cascade and (2) the mechanism of nuclear transport. The nuclear transport of transcription factors, nuclear kinases, steroid hormone receptors, and replication factors often serves a critical regulatory function. We are examining the mechanisms of nuclear import, export, and subnuclear targeting. We identified a novel nuclear transport pathway involving calmodulin. This pathway has been shown to play a role in mammalian sex determination and stem cell differentiation. We are identifying additional components of this pathway using yeast genetics and chemical biology approaches.
The nuclear pore complex (NPC) mediates the transport of mRNA and proteins across the nuclear envelope. Many components of the nuclear pore are modified by a novel modification: O-linked N-acetylglucosamine (O-linked GlcNAc). The modification also occurs on transcription factors and certain oncogenes and tumor suppressors. Current evidence suggests that the O-linked GlcNAc transferase (OGT) mediates a novel glycan-dependent signal transduction pathway. We have molecularly cloned and characterized the human OGT responsible for glycosylating nuclear pore proteins. This enzyme is expressed as differentially targeted isoforms in man and is localized to both the nucleus and the mitochondria. When expressed in E. coli, the human OGT is catalytically active. We recently solved the X-ray structure of the substrate recognition domain of OGT and we are beginning to understand how it recognizes its many intracellular targets. Although the enzyme is found in a number of target tissues, it is most highly expressed in human pancreatic beta cells, consistent with a role in glucose-sensing. Based on its substrate specificity and molecular features, we have proposed that OGT is the terminal step in a glucose-responsive pathway that becomes dysregulated in diabetes mellitus (NIDDM).
Hanover JA, Krause MW, Love DC. Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nat Rev Mol Cell Biol. 2012;13(5):312-21.
Ranuncolo SM, Ghosh S, Hanover JA, Hart GW, Lewis BA. Evidence of the involvement of O-GlcNAc-modified human RNA polymerase II CTD in transcription in vitro and in vivo. J Biol Chem. 2012;287(28):23549-61.
Mondoux MA, Love DC, Ghosh SK, Fukushige T, Bond M, Weerasinghe GR, Hanover JA, Krause MW. O-linked-N-acetylglucosamine cycling and insulin signaling are required for the glucose stress response in Caenorhabditis elegans. Genetics. 2011;188(2):369-82.
Hanover JA. A versatile sugar transferase makes the cut. Cell. 2011;144(3):321-3.
Keembiyehetty CN, Krzeslak A, Love DC, Hanover JA. A lipid-droplet-targeted O-GlcNAcase isoform is a key regulator of the proteasome. J Cell Sci. 2011;124(Pt 16):2851-60.