William G. Kaelin Jr.

William Kaelin Jr. is a Professor at Dana-Farber Cancer Institute and Harvard Medical School, and a Howard Hughes Medical Institute Investigator. He is a co-recipient of the 2019 Nobel Prize in Physiology or Medicine (shared with Peter Ratcliffe and Gregg Semenza) for the discovery of how cells sense and adapt to oxygen availability — one of the most fundamental physiological mechanisms in all of eukaryotic biology, with profound implications for cancer, cardiovascular disease, and ischemia. Kaelin's entry into this field came through his work on the VHL (von Hippel-Lindau) tumor suppressor protein. VHL mutations cause VHL disease — a hereditary cancer syndrome characterized by hemangioblastomas, clear cell renal cell carcinoma (ccRCC), and pheochromocytoma — and VHL is mutated or silenced in the vast majority of sporadic clear cell renal cell carcinomas. Kaelin's laboratory discovered that VHL's primary tumor-suppressive function is to act as a substrate recognition subunit of an E3 ubiquitin ligase complex that targets HIF-1α and HIF-2α (hypoxia-inducible factors) for proteasomal degradation. In the presence of sufficient oxygen, specific proline residues on HIF-α subunits are hydroxylated by prolyl hydroxylase (PHD) enzymes, creating a binding site for VHL. VHL then recruits ubiquitin ligase machinery to poly-ubiquitinate HIF-α, targeting it for degradation. In hypoxia — or when VHL is mutated — HIF-α escapes degradation, dimerizes with HIF-1β, and transcriptionally activates hundreds of genes involved in angiogenesis (VEGF, PDGF), glucose metabolism (GLUT1, LDHA), erythropoiesis (EPO), and cell survival. Kaelin, working in parallel with Ratcliffe and Semenza, collaboratively assembled the complete molecular machinery of oxygen sensing. This discovery has had immediate and far-reaching clinical consequences. The molecular pathway Kaelin elucidated became the basis for the development of HIF-2α inhibitors for VHL-mutated renal cell carcinoma: belzutifan (MK-6482, a HIF-2α inhibitor developed in part based on Kaelin's structural studies) received FDA approval in 2021 for VHL disease-associated ccRCC — representing a direct, traceable line from Nobel Prize-winning basic science to approved therapy. PHD inhibitors (roxadustat, daprodustat) that activate HIF to stimulate erythropoietin production are approved for anemia of chronic kidney disease. Kaelin also made major contributions to understanding E2F transcription factor biology and how RB1 tumor suppressor protein controls cell cycle progression by repressing E2F target genes — work that built on and extended the foundational retinoblastoma biology established by Weinberg and Jacks.

William Kaelin Jr. 是丹娜-法伯癌症研究所和哈佛医学院的医学教授，以及霍华德·休斯医学研究所研究员。他与 Peter Ratcliffe 和 Gregg Semenza 共同荣获2019年诺贝尔生理学或医学奖，以表彰他们发现细胞感知和适应氧气可用性的方式。 Kaelin 的实验室发现，VHL蛋白的主要肿瘤抑制功能是作为E3泛素连接酶复合物的底物识别亚基，该复合物靶向HIF-1α和HIF-2α进行蛋白酶体降解。这一发现在临床上产生了直接影响：HIF-2α抑制剂belzutifan于2021年获FDA批准用于VHL病相关肾细胞癌，代表了从诺贝尔奖获奖基础科学到批准疗法的直接可追溯路径。