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Dr. Greengard’s Briefcase
No full textDr. Greengard’s briefcase
Courtesy of Greengard\u27s laboratory
Paul Greengard (1925-2019) was a neurologist and Nobel Prize winner whose seven-decade career transformed our understanding of neuroscience. His discoveries laid out a new paradigm requiring the understanding of the biochemistry of nerve cells rather than simply their electrical activities. This work has had a great impact. Today, abnormalities in signaling among neurons are recognized to underlie many neurologic and psychiatric disorders including Parkinson’s disease, schizophrenia, depression, attention deficit hyperactivity disorder, and substance abuse.
Dr. Greengard donated his entire monetary share of the 2000 Nobel Prize in Physiology or Medicine to Rockefeller and, in partnership with generous supporters of the University, established the Pearl Meister Greengard Prize. Named in memory of his mother, who died giving birth to him, this major international prize recognizes the accomplishments of outstanding women scientists.https://digitalcommons.rockefeller.edu/objects-tell-stories/1034/thumbnail.jp
A Celebration of the Life of Dr. Mary Jeanne Kreek
Get PDFProgram. A Celebration of the life of Dr. Mary Jeanne Kreek. Thursday, May 26, 2022https://digitalcommons.rockefeller.edu/artifacts-ephemera/1028/thumbnail.jp
Uncovering Regulators of Whole-Body Metabolism by Chemoproteomic Profiling of the Adipocyte Secretome
Get PDFA major threat to human health, obesity is associated with increased risk of cardiometabolic complications such as cardiovascular disease, type 2 diabetes, hypertension, and many types of cancers. Whereas white adipocytes efficiently store energy in the form of triglycerides, thermogenic brown and beige adipocytes can dissipate energy into heat. Adipose tissue is now considered an important endocrine organ, and increasing evidence suggests that divergent metabolic effects of different types of adipocytes are in part mediated by their secretory function. In addition, dysregulation of adipose tissue\u27s secretory function in the setting of chronic positive energy balance plays a central role in the pathophysiology of obesity and its complications. However, the vast majority of bioactive peptides secreted by adipose tissue, collectively referred to as adipokines, remain uncharacterized. We employed bio-orthogonal non-canonical amino acid tagging (BONCAT) and mass spectrometry to comprehensively characterize the secretome of murine visceral and subcutaneous white adipocytes and interscapular brown adipocytes. Over 600 proteins were identified, the majority of which showed cell type specificity with functional enrichment. BONCAT was also applied in vivo to label and characterize the nascent serum proteome of mice, and bioinformatic analyses suggested that adipose tissue is an important contributor to the serum proteome. We here describe two candidate adipokines identified from these profiling studies, C11orf54 and leucine-rich α-2 glycoprotein 1 (LRG1). C11orf54 was shown to be a cold-induced, brown/beige enriched protein. Despite the lack of a signal peptide, the long isoform (isoform 1) of C11orf54 was validated to be a bona fide secreted factor, while the short isoform (isoform 2) was predominantly intracellular. Functional studies with mice lacking C11orf54 isoform 1 suggest that it may regulate total body energy expenditure. Further studies will be performed to validate and decipher the molecular mechanism underlying this physiological effect. LRG1 was identified as an obesity-regulated adipokine secreted by mature adipocytes. Plasma LRG1 levels were increased in aged and diet-induced obese (DIO) mice. LRG1 overexpression significantly improved glucose and insulin tolerance in DIO mice, despite equivalent body weights. AAV-mediated longitudinal overexpression of LRG1 in the db/db model of type 2 diabetes resulted in accelerated weight gain due to increased white fat mass, but improved insulin tolerance and a delayed diabetic phenotype. This effect was associated with markedly reduced macrophage accumulation in white adipose tissues and a dramatic reduction in systemic inflammation. At the molecular level, LRG1 was shown to bind extracellular cytochrome c (Cyt c), whose levels in serum increased with both diet-induced and genetic obesity. LRG1\u27s ability to bind Cyt c led to dampening of Cyt c\u27s pro-inflammatory effect on the macrophage innate immune signaling pathway. These data support a new role for LRG1 as an insulin sensitizer and modulator of inflammation with therapeutic potential. Overall, the work described here provides a thorough characterization of the secretome of white and brown adipocytes, and functional studies on previously undescribed adipokines elucidate novel mechanisms at the intersection of obesity, inflammation, and associated pathology
East Walk in Fall
No full textEast Walk in fall, 2022
Photo by Juan Rodriguezhttps://digitalcommons.rockefeller.edu/campus/1092/thumbnail.jp
Welch\u27s Birthplace in Norfolk, Connecticut
No full textWilliam Welch\u27s birthplace in Norfolk, Connecticut. On the porch - his father, William Wickham Welch
Source of the photograph: Simon Flexner, James T. Flexner. William Henry Welch and the Heroic Age of American Medicine, 1941https://digitalcommons.rockefeller.edu/jem-the-beginnings/1001/thumbnail.jp
Welch\u27s Letter to Alexander C. Abott
No full textIn this letter of November 24, 1895, William H. Welch reminds his colleague, Alexander C. Abott, of the University of Pennsylvania, of the soon to be published Journal of Experimental Medicine. The journal, of which Welch was founding editor, did commence the following year and is still in publication.
Courtesy of Medical Archives of The Johns Hopkins Medical Institutionshttps://digitalcommons.rockefeller.edu/jem-the-beginnings/1011/thumbnail.jp
Details of the Exhibit
No full textDetails of the exhibit JEM: The Beginnings
Idea, design: Olga Nilova, Special Collections Librarian
Photo by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/jem-the-beginnings/1014/thumbnail.jp
Details of the Exhibit
No full textDetails of the exhibit JEM: The Beginnings
March 8, 1902, was a banner day in Flexner’s career. By unanimous vote of the board, he was asked “to consider under what circumstances he would be induced to take charge of the laboratory.” He agreed to prepare for submission to the board a statement concerning the establishment and organization of such a permanent home for the institution as would lead him to consider favorably the post of director. – James T. Flexner. An American saga. New York, 1993
Idea, design - Olga Nilova, Special Collections Librarian
Photo by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/jem-the-beginnings/1029/thumbnail.jp
Transcriptional Regulation of the Metabolic Response to Therapy in Leukemia
Get PDFCancer cells are under constant stress due to their uncontrolled growth, oncogenic signaling, and the metabolic insufficiencies of their microenvironments. Under various stresses, cells activate the integrated stress response (ISR), a transcriptional program to restore cellular homeostasis. Activating transcription factor 4 (ATF4) acts as the master transcriptional regulator of the ISR by promoting the transcription of genes that mitigate stress or promote cell death if the stress remains unresolved. Despite being the common mediator of various stress response and metabolic pathways, ATF4 generates tailored transcriptional outputs to distinct cellular stresses by cooperating with other transcriptional machinery. The precise mechanisms by which ATF4 activates an appropriate transcriptional program in response to metabolic stresses, however, remain unclear. In this work, we used forward genetic screens, metabolic profiling, and biochemical approaches to identify transcriptional regulators required for the cellular response to various metabolic stress conditions. This work revealed that ATF4 is universally required under amino acid starvation, but identified the transcription factor, Zinc Finger and BTB domain-containing protein 1 (ZBTB1), as a critical regulator of the response to asparagine deprivation in acute lymphoblastic leukemia (ALL). We found that under asparagine depleted conditions ZBTB1 enables cellular proliferation by promoting the synthesis of asparagine from aspartate. Mechanistically, ZBTB1 binds directly to a sequence within the promoter of asparagine synthetase (ASNS), the enzyme responsible for the synthesis of asparagine from aspartate. Loss of ZBTB1 results in a dramatic reduction in the transcription of ASNS, and, subsequently, a reduced capacity for cells to synthesize asparagine from aspartate. ZBTB1 knockout T-ALLs are not only sensitive to asparagine deprivation in vitro but are also sensitive to treatment with L-asparaginase, a chemotherapy that reduces serum asparagine, in in vivo xenograft models of ALL. Additionally, this work clarifies the metabolic stress induced by CPI-613, a lipoic acid analog designed to inhibit the function of Pyruvate Dehydrogenase (PDH), the enzyme responsible for the decarboxylation of pyruvate to acetyl-CoA. In line with the proposed mechanism of CPI-613, genetic screens suggested a synthetic lethal relationship between electron transport chain or TCA cycle enzymes and CPI-613. Unexpectedly, however, glycerolipid synthesis genes were found to be essential for the cellular response to CPI-613-induced stress. Further work revealed a substantial incorporation of CPI-613 into glycerolipid species, a finding that correlates with sensitivity to the drug. Altogether, our work defines novel metabolic and transcriptional mechanisms of the response of acute leukemias to metabolic stresses. In acute lymphoblastic leukemia, we have identified a critical transcriptional regulator of the cellular response to asparagine deprivation. The role of ZBTB1 in the transcriptional regulation of ASNS in parallel with ATF4 has direct relevance to the therapeutic response of ALLs to Lasparaginase. We have also determined a novel mechanism of action of CPI-613, a first-in-class PDH inhibitor currently in phase III clinical trials for acute myeloid leukemia (AML). This work revealed the incorporation of CPI-613 into glycerolipid species which may be relevant to toxicity of the drug. Altogether this work provides a framework for investigating the metabolic and transcriptional mechanisms by which leukemias respond to cellular stresses such as those induced by metabolically targeted therapies
Deciphering Cancer Metabolic Dependencies in the Tumor Microenvironment
Get PDFCancer cells face substantial pressure within the tumor microenvironment. Physical constraints and nutrient limitations in the tumor prevent excessive cell proliferation, while other cell types such as stromal and immune cells can compete with or kill cancer cells. To overcome these restrictions, cancer cells often possess oncogenic mutations or amplifications to divide rapidly but can also rewire their metabolism in adaptation to the environmental challenge. The metabolism of cancer cells exhibit high plasticity as many metabolic pathways and enzymes are redundant. This allows for cancer cells to adapt to the changing nutritional and intercellular context of the tumor. Though metabolic rewiring helps cancer cells survive and grow, the resultant reliance on specific metabolites or pathways present opportunities for therapeutic intervention. Recent advances in cancer metabolism have focused on characterizing these metabolic dependencies in different tumor contexts. This work employs unbiased CRISPR-guided genetic screens and large-scale metabolomics analyses to identify the metabolic dependencies of cancer cells under lipid saturation stress and characterize the in vivo specific metabolic liabilities of pancreatic tumors. Cells require a constant supply of fatty acids to survive and proliferate but excess levels of fatty acids, specifically saturated lipids, are toxic to cells. However, the molecular mechanism of this toxicity is not well understood though this phenomenon is implicated in hypoxic tumors as cells require oxygen to desaturate fatty acids. Fatty acids incorporate into membrane and storage glycerolipids through a series of endoplasmic reticulum (ER) enzymes, but how these enzymes are regulated and how they contribute to lipid toxicity are also not well understood. With a combination of CRISPR-based genetic screens and unbiased lipidomics, we identified calcineurin B homologous protein 1 (CHP1) as a major regulator of ER glycerolipid synthesis and saturated lipid toxicity. Mechanistically, CHP1 binds and activates GPAT4, which catalyzes the initial rate-limiting step in glycerolipid synthesis. GPAT4 activity requires CHP1 to be N-myristoylated, forming a key molecular interface between the two proteins. Interestingly, upon CHP1 loss, the peroxisomal enzyme, GNPAT, partially compensates for the loss of ER lipid synthesis, enabling cell proliferation. Loss of CHP1 severely reduces fatty acid incorporation and storage in mammalian cells and invertebrates. Depletion of Chp1 and Gpat4 in the mouse liver reduces steatosis and inflammation during fatty liver disease. Our work identified a conserved regulator of glycerolipid metabolism and revealed metabolic regulators of cancer cells under saturated lipid toxicity. To probe for similar lipid saturation stress and characterize the major metabolic dependencies of tumor growth in its endogenous microenvironment, we optimized our CRISPR screening approach on pancreatic ductal adenocarcinoma (PDAC). PDAC cells require substantial metabolic rewiring to overcome nutrient limitations and immune surveillance. However, the metabolic pathways necessary for pancreatic tumor growth in vivo are poorly understood. To address this, we performed metabolism-focused CRISPR screens in PDAC cells grown in culture or engrafted in immunocompetent mice. While most metabolic gene essentialities are unexpectedly similar under these conditions, a small fraction of metabolic genes are differentially required for tumor progression. Among these, loss of heme synthesis reduces tumor growth due to a limiting role of heme in vivo, an effect independent of tissue origin or immune system. Our screens also identify autophagy as a metabolic requirement for pancreatic tumor immune evasion. Mechanistically, autophagy protects cancer cells from CD8+ T cell killing through TNFα-induced cell death in vitro. Altogether, the in vivo screens provide metabolic dependencies arising from microenvironmental limitations and the immune system, nominating potential anti-cancer targets. Overall, this work provides a framework to identify the molecular mechanisms of specific metabolic liabilities and unbiasedly decipher the metabolic dependencies of cancer cells in the tumor microenvironment