Abstract #386
Section: Cell Biology Symposium
Session: Cell Biology Symposium: Regulation of growth through amino acid sensing
Format: Oral
Day/Time: Tuesday 10:15 AM–11:00 AM
Location: Panzacola F-4
Session: Cell Biology Symposium: Regulation of growth through amino acid sensing
Format: Oral
Day/Time: Tuesday 10:15 AM–11:00 AM
Location: Panzacola F-4
# 386
Integration of amino acid signaling and metabolism in the mTORC1 pathway.
John Blenis*1, Gwen Buel1, Anders Mutvei1, Alfredo Csibi1, Jing Li1, Gina Lee1, Sang Gyun Kim1, Andy Choo1, 1Sandra and Edward Meyer Cancer Center, Department of Pharmacology, Belfer Research Building, Weill Cornell Medical College, New York, NY.
Key Words: mTOR complex, amino acid signaling, cellular metabolism
Speaker Bio
Integration of amino acid signaling and metabolism in the mTORC1 pathway.
John Blenis*1, Gwen Buel1, Anders Mutvei1, Alfredo Csibi1, Jing Li1, Gina Lee1, Sang Gyun Kim1, Andy Choo1, 1Sandra and Edward Meyer Cancer Center, Department of Pharmacology, Belfer Research Building, Weill Cornell Medical College, New York, NY.
The mTOR complex 1 (mTORC1) signaling pathway has evolved to sense and respond to amino acid availability, cellular energy status, surrounding oxygen concentrations and stress conditions. In addition, mTORC1 can be further activated by mitogen- and hormone-stimulated kinases including Akt, ERK, and RSK, and suppressed by mTORC1-regulated S6K1 via a variety of negative feedback loops. The integration of these multiple inputs control the strength and duration of downstream signaling, which is important in differentially regulating mTORC1-dependent processes such as protein synthesis and cellular metabolism. Importantly, amino acid-mediated regulation of mTORC1 is reportedly dominant over mitogen-dependent activation of mTORC1 signaling and therefore has attracted much interest as a therapeutic target in mTORC1-driven diseases such as obesity, diabetes, aging, and cancer. The molecular basis for amino acid signaling is complex but many gaps in our knowledge of this regulatory system remain. We will discuss our recent observations regarding amino acid-dependent regulation of mTORC1 and the ability of mTORC1 to regulate cellular metabolism.
Key Words: mTOR complex, amino acid signaling, cellular metabolism
Speaker Bio
The research of Dr. John Blenis, the newly appointed Anna Maria and Stephen Kellen Professor of Cancer Research and Professor of Pharmacology in the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College, is aimed at defining critical signal transduction mechanisms and how altered cellular signaling promotes carcinogenesis. While at Harvard Medical School, Dr. Blenis discovered that Ras connected tyrosine kinases to the serine/threonine kinases Raf, ERK-MAP kinase and RSK, and that activated ERK and RSK translocate to the nucleus. These studies provided the molecular framework for how signals from outside the cell transverse the cytoplasm to the nucleus to coordinate the regulation of gene expression, cell migration survival, metabolism and proliferation. He then discovered several molecular sensors that convert subtle differences in ERK activity and cell location into specific biological responses such as EMT and metastasis. Dr. Blenis also discovered the link between tyrosine kinases, PI3-kinases (PI3K) and serine/threonine S6 kinase (S6K), and that S6K activation is blocked by the mTOR inhibitor and natural product, rapamycin. Rapalogs are now in several preclinical and clinical trials for both monotherapy and combination strategies. Dr. Blenis is continuing to define how mTOR/S6K regulates cell metabolism, gene expression, mRNA processing, protein synthesis and cell growth.
By defining the signaling landscape surrounding the Ras/ERK and PI3K/mTOR pathways, the research from Dr. Blenis' lab has supported the identification of cancer-associated biomarkers and therapeutic targets including several kinases and metabolic enzymes, which are now candidates for cancer therapy. His laboratory is also investigating the molecular mechanisms leading to the development of drug resistance to targeted therapies with the goal of discovering how to overcome resistance. As part of this program, his laboratory has developed and completed several small molecule screens that have revealed potential combination approaches for selectively killing cancer cells.
-----------------------------------------------
In the past 25 years as a faculty member, Dr. Blenis has trained or is currently training 40 postdoctoral fellows and 17 graduate students. Several of the past trainees are now in independent academic positions at major research universities and institutes including Yale University, University of Pennsylvania, University of Michigan, Seoul National University, Academia Sinica, Tufts University, University of Washington, Yeshiva University-Albert Einstein College of Medicine, the Van Andle Institute, University of Vermont, University of Montreal and University of Texas, Southwestern Medical Center. Several others hold senior positions in the biopharmaceutical industry. The Blenis Lab currently has 2 graduate students, 8 postdoctoral fellows, 2 research assistants, 2 instructors and 1 research assistant professor.
By defining the signaling landscape surrounding the Ras/ERK and PI3K/mTOR pathways, the research from Dr. Blenis' lab has supported the identification of cancer-associated biomarkers and therapeutic targets including several kinases and metabolic enzymes, which are now candidates for cancer therapy. His laboratory is also investigating the molecular mechanisms leading to the development of drug resistance to targeted therapies with the goal of discovering how to overcome resistance. As part of this program, his laboratory has developed and completed several small molecule screens that have revealed potential combination approaches for selectively killing cancer cells.
-----------------------------------------------
In the past 25 years as a faculty member, Dr. Blenis has trained or is currently training 40 postdoctoral fellows and 17 graduate students. Several of the past trainees are now in independent academic positions at major research universities and institutes including Yale University, University of Pennsylvania, University of Michigan, Seoul National University, Academia Sinica, Tufts University, University of Washington, Yeshiva University-Albert Einstein College of Medicine, the Van Andle Institute, University of Vermont, University of Montreal and University of Texas, Southwestern Medical Center. Several others hold senior positions in the biopharmaceutical industry. The Blenis Lab currently has 2 graduate students, 8 postdoctoral fellows, 2 research assistants, 2 instructors and 1 research assistant professor.
