William G. Kaelin
Harvard University
Molecular biologyCancer researchGeneticsTranscription factorBiology
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Publications 332
#1Jennifer CableH-Index: 1
#2Lydia W. S. Finley (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 21
Last. William G. Kaelin (Harvard University)H-Index: 110
view all 14 authors...
Tumor cells have devised unique metabolic strategies to garner enough nutrients to sustain continuous growth and cell division. Oncogenic mutations may alter metabolic pathways to unlock new sources of energy, and cells take the advantage of various scavenging pathways to ingest material from their environment. These changes in metabolism result in a metabolic profile that, in addition to providing the building blocks for macromolecules, can also influence cell signaling pathways to promote tumo...
#1Hua Zhang (NYU: New York University)H-Index: 3
#2Camilla L. Christensen (Harvard University)H-Index: 16
Last. Kwok-Kin Wong (NYU: New York University)H-Index: 84
view all 49 authors...
Summary Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events p...
6 CitationsSource
#1Hilary E. Nicholson (Harvard University)H-Index: 1
#1Hilary E. Nicholson (Harvard University)H-Index: 2
Last. William G. Kaelin (HHMI: Howard Hughes Medical Institute)H-Index: 110
view all 4 authors...
Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene and its protein product, pVHL, occurs in ~90% of clear cell renal cell carcinoma (ccRCC) cases. pVHL is part of the ubiquitin ligase complex that targets the HIF2α transcription factor, an oncoprotein in ccRCC, for proteasomal degradation. Without functional pVHL, HIF2α accumulates and induces inappropriate transcription of angiogenic, invasive, and growth-promoting genes. Drugs inhibiting HIF2α or its downstream target VEGF are a...
#1Matthew Oser (Harvard University)H-Index: 12
#2Amin H. Sabet (Brigham and Women's Hospital)H-Index: 1
Last. William G. Kaelin (Brigham and Women's Hospital)H-Index: 110
view all 21 authors...
More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1 The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expre...
2 CitationsSource
#1Hilary E. Nicholson (Harvard University)H-Index: 1
#2Zeshan Tariq (Harvard University)H-Index: 1
Last. William G. Kaelin (Harvard University)H-Index: 110
view all 8 authors...
Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, and causes the accumulation of hypoxia-inducible factor 2α (HIF-2α). HIF-2α inhibitors are effective in some ccRCC cases, but both de novo and acquired resistance have been observed in the laboratory and in the clinic. Here, we identified synthetic lethality between decreased activity of cyclin-dependent kinases 4 and 6 (CDK4/6) and VH...
3 CitationsSource
#1Shuijie Li (KI: Karolinska Institutet)H-Index: 4
#2Javier Rodríguez Velásquez (Edin.: University of Edinburgh)H-Index: 30
Last. Susanne Schlisio (KI: Karolinska Institutet)H-Index: 12
view all 18 authors...
Despite the discovery of the oxygen-sensitive regulation of HIFα by the von Hippel–Lindau (VHL) protein, the mechanisms underlying the complex genotype/phenotype correlations in VHL disease remain unknown. Some germline VHL mutations cause familial pheochromocytoma and encode proteins that preserve their ability to down-regulate HIFα. While type 1, 2A, and 2B VHL mutants are defective in regulating HIFα, type 2C mutants encode proteins that preserve their ability to down-regulate HIFα. Here, we ...
#1Nilay SethiH-Index: 9
#2Osamu KikuchiH-Index: 23
Last. Adam J. BassH-Index: 37
view all 11 authors...
#1Isaac S. Harris (Harvard University)H-Index: 20
#2Jennifer E. Endress (Harvard University)H-Index: 1
Last. Joan S. Brugge (Harvard University)H-Index: 102
view all 21 authors...
Summary Cells are subjected to oxidative stress during the initiation and progression of tumors, and this imposes selective pressure for cancer cells to adapt mechanisms to tolerate these conditions. Here, we examined the dependency of cancer cells on glutathione (GSH), the most abundant cellular antioxidant. While cancer cell lines displayed a broad range of sensitivities to inhibition of GSH synthesis, the majority were resistant to GSH depletion. To identify cellular pathways required for thi...
4 CitationsSource
#1Abhishek A. Chakraborty (Brigham and Women's Hospital)H-Index: 10
#2Tuomas Laukka (University of Oulu)H-Index: 4
Last. William G. Kaelin (Brigham and Women's Hospital)H-Index: 110
view all 19 authors...
Oxygen sensing is central to metazoan biology and has implications for human disease. Mammalian cells express multiple oxygen-dependent enzymes called 2-oxoglutarate (OG)-dependent dioxygenases (2-OGDDs), but they vary in their oxygen affinities and hence their ability to sense oxygen. The 2-OGDD histone demethylases control histone methylation. Hypoxia increases histone methylation, but whether this reflects direct effects on histone demethylases or indirect effects caused by the hypoxic induct...
20 CitationsSource
#1Vidyasagar Koduri (Harvard University)H-Index: 4
#2Samuel K. McBrayer (Harvard University)H-Index: 9
Last. William G. Kaelin (Harvard University)H-Index: 110
view all 7 authors...
Current systems for modulating the abundance of proteins of interest in living cells are powerful tools for studying protein function but differ in terms of their complexity and ease of use. Moreover, no one system is ideal for all applications, and the best system for a given protein of interest must often be determined empirically. The thalidomide-like molecules (collectively called the IMiDs) bind to the ubiquitously expressed cereblon ubiquitin ligase complex and alter its substrate specific...