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This year’s Lasker Basic Medical Research Award is shared by William Kaelin, Peter Ratcliffe, and Gregg Semenza for discovery of the pathway by which animal cells sense and adapt to changes in oxygen availability, which plays an essential role in adaptation to a wide variety of physiologic and pathologic conditions.
Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth...
Despite being surrounded by diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids. Recently, Ras-induced macropinocytosis of extracellular proteins was shown to reduce a transformed cell’s dependence on extracellular glutamine. Here, we demonstrate that protein macropinocytosis can also serve as an essential amino acid source. Lysosomal degradation of extracellular...
An understanding of metabolic pathways based solely on biochemistry textbooks would underestimate the pervasive role of metabolism in essentially every aspect of biology. It is evident from recent work that many human diseases involve abnormal metabolic states—often genetically programmed—that perturb normal physiology and lead to severe tissue dysfunction. Understanding these metabolic outliers is...
Mechanisms that regulate cellular metabolism are a fundamental requirement of all cells. Most eukaryotic cells rely on aerobic mitochondrial metabolism to generate ATP. Nevertheless, regulation of mitochondrial activity is incompletely understood. Here we identified an unexpected and essential role for constitutive InsP 3 R-mediated Ca 2+ release in maintaining cellular bioenergetics...
This year the Lasker DeBakey Clinical Research Award will be shared by Brian Druker, Nicholas Lydon, and Charles Sawyers for their development of a targeted molecular therapy for treating chronic myeloid leukemia. Their work demonstrated the ability of drugs directed against cancer-causing oncogenes to turn a rapidly fatal malignancy into a manageable chronic disease.
Intrinsic immune responses autonomously inhibit viral replication and spread. One pathway that restricts viral infection in plants and insects is RNA interference (RNAi), which targets and degrades viral RNA to limit infection. To identify additional genes involved in intrinsic antiviral immunity, we screened Drosophila cells for modulators of viral infection using an RNAi library. We identified Ars2...
Here we identify a component of the nuclear RNA cap-binding complex (CBC), Ars2, that is important for miRNA biogenesis and critical for cell proliferation. Unlike other components of the CBC, Ars2 expression is linked to the proliferative state of the cell. Deletion of Ars2 is developmentally lethal, and deletion in adult mice led to bone marrow failure whereas parenchymal organs composed of nonproliferating...
In animals, cells are dependent on extracellular signals to prevent apoptosis. However, using growth factor-dependent cells from Bax/Bak-deficient mice, we demonstrate that apoptosis is not essential to limit cell autonomous survival. Following growth factor withdrawal, Bax -/- Bak -/- cells activate autophagy, undergo progressive atrophy, and ultimately succumb...
Apoptosis plays a critical role in lymphocyte development and homeostasis. Enhanced lymphocyte apoptosis can cause immunodeficiency through cell loss. Conversely, inhibition of apoptosis can lead to the development of autoimmunity or lymphoma. Two major pathways contribute to the regulation of lymphocyte cell death, death-by-neglect and death-by-instruction.
Mitochondrial physiology is disrupted in either apoptosis or necrosis. Here, we report that a wide variety of apoptotic and necrotic stimuli induce progressive mitochondrial swelling and outer mitochondrial membrane rupture. Discontinuity of the outer mitochondrial membrane results in cytochrome c redistribution from the intermembrane space to the cytosol followed by subsequent inner mitochondrial...
To extend the mammalian cell death pathway, we screened for further Bcl-2 interacting proteins. Both yeast two-hybrid screening and λ expression cloning identified a novel interacting protein, Bad, whose homology to Bcl-2 is limited to the BH1 and BH2 domains. Bad selectively dimerized with BCl-x L as well as Bcl-2, but not with Bax, Bcl-x S , Mcl-1, A1, or itself. Bad binds more strongly...
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