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In Memoriam: Kazuhiko Umesono (1958–1999)

Howard Hughes Medical Institute, Professor, The Salk Institute for Biological Studies

April marks the first anniversary of the passing of Dr. Kazuhiko Umesono, one of the brightest stars of the nuclear receptor field, who helped transform our understanding of the signaling mechanisms of nuclear hormones. He was only 41 yr old, and with his death the world has lost a uniquely insightful and creative force.

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In 1987 Kaz joined my laboratory. It was a pivotal time, as a group of remarkable graduate students and postdocs had just cloned the glucocorticoid (GR), mineralocorticoid (MR), and thyroid (TR) hormone receptors and were in the process of completing the sequence of the retinoic acid receptor (RAR). Kaz, who was passionate and commanding in his work, immediately set out to decipher how these receptors—as hormone-dependent transcription factors—recognize their target genes. His very first paper, published in Nature in 1988, was prescient as it described the core DNA signature motifs for the TR and RAR and revealed the necessity of a competence factor from a nuclear extract to facilitate the binding. The missing component, yet to be discovered, was the retinoid receptor (RXR). He next attacked the receptor-coding mechanism, which led to the identification of the so-called "P box" and "D box" in the DNA-binding domain. The P box, now known to be part of the major recognition helix, determined primary sequence recognition, while the D box controlled a novel dimerization function. A single amino acid change in the P box enabled a glucocorticoid receptor to bind an estrogen response element. The clarity of the work suggested that the P box itself would be predictive of the target recognition sequence in DNA. Kaz understood, well before the rest of us, that this work created a paradox since most receptors harbored either a GR type or ER type P box. Thus, how could one explain their regulation of a diversity of target genes? Perhaps the answer was in the D box or dimerization motif, which was unique for each receptor.

It was this remarkable idea that led to the spacing paradigm for hormone response elements, termed the 3-4-5 rule. He first recognized and proved that many response elements are comprised of direct repeats (DRs), then established that specificity could be achieved by unique spacing of common half-sites. Suddenly it was clear—a vitamin D₃ response element was a DR-3 (direct repeat spaced by 3 nucleotides), a DR-4 for thyroid hormone, and a DR-5 for retinoic acid. Once David Mangelsdorf discovered RXR, Umesono quickly and correctly theorized it would act through a DR-1 target. With Steve Kliewer, he helped discover that the magic nuclear ingredient for receptor binding was RXR and, with Thomas Perlmann, helped to characterize its properties.

Of his many collaborations, perhaps that with Ruth Yu was the most important. This led to a Nature paper on the orphan receptor TLX, a homolog of the Drosophila gap gene "tailless." This collaboration evolved from science to a friendship to love and marriage. In 1994, after 10 Nature and Cell papers and a total of 24 manuscripts, Kaz returned to Japan as Associate Professor at the Nara Institute of Science and Technology. In 1997 he became Professor of the Institute for Virus Research and Graduate School of Biological Sciences at Kyoto University. In the short time since his return he published 16 papers, including the cloning of a novel eye-specific orphan receptor, the long-sought-after retinol dehydrogenase that establishes positional information in the retina and discovered a unique role for TLX in eye development.

Kazuhiko Umesono was a true scientist, brilliant and creative. Words cannot describe what an honor it was to know and work with Kaz. He was a force that spun a web of vitality throughout the lab that connected many of us in a deep and personal way. His science was bold, and we were touched by his personal and intellectual generosity, which enriched us all. He sacrificed and devoted himself to its pursuit. His forte was working on these problems with colleagues who were energized by his enthusiasm and ideas. He was a shining star who inspired us, and it is that spirit which will continue to light our way.

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