The life (and death) of cells
The development and maintenance of normal tissues and organs requires careful coordination between numerous distinct cell types. For early growth and development, cells need to proliferate and differentiate extensively to provide the specialized functions and structures of different organs. Subsequently, small populations of stem cells provide a constant supply of new cells to replenish dying cells within a tissue and maintain normal organ function. Not surprisingly, defects in any of these basic cellular processes can lead to disease. Most notably, uncontrolled cell proliferation, a block in cell differentiation, or the failure to initiate programmed cell death are often hallmarks of cancer.
MCCB researchers focus on all of these basic aspects of cell biology and their mis-regulation in disease settings. In this regard, MCCB researchers rely on a variety of model systems, including fruit fly, mouse, yeast, and zebrafish to study autophagy, cell proliferation, differentiation, migration, and programmed cell death. Click on the links below to see more details concerning work in this area.
Involution is the process by which the mammary gland returns to its non-lactating state, via weaning-induced cell death of milk-producing alveolar cells. The ubiquitin ligase RLIM functions as a critical survival factor specifically for the alveolar cell type in mammary glands of pregnant and lactating female mice. Research in the Bach lab aims to elucidate the molecular mechanisms of how RLIM promotes alveolar cell survival and how involution is triggered upon weaning.
Autophagy is a process of “self-eating” that cells use to clear material and maintain their overall health and function. The Baehrecke laboratory studies how autophagy is regulated and functions in complex multi-cellular organisms using the fruit fly as a model system. Researchers in the laboratory screen for novel mechanisms that control autophagy and determine how autophagy functions to promote cell health and cell death in different cells and tissues within animals.
- Berry DL, Baehrecke EH. (2007) Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell, 131(6):1137-48
- McPhee et al. (2010) Activation of autophagy during cell death requires the engulfment receptor Draper. Nature, 465(7301):1093-6.
- Chang et al. (2013) Uba1 functions in Atg7- and Atg3-independent autophagy. Nat Cell Biol, 15(9):1067-78.
- Nelson et al. (2014) miR-14 regulates autophagy during developmental cell death by targeting ip3-kinase 2. Mol Cell, 56(3):376-88.
Protein degradation via the ubiquitin-proteasome system is essential for cells to grow and divide. Consistent with this role, numerous ubiquitin ligases (E3s) that promote protein degradation, as well as deubiquitinating enzymes (DUBs) that antagonize E3 function, are mutated in cancer cells. However, the targets of most of these enzymes remain unknown. The Benanti Lab is using yeast as a model system to determine how conserved E3s and DUBs recognize and select their substrates, and to develop proteome-wide approaches to identify targets of these critical enzymes.
The homeostatic balance of life and death of cells is critical for the well-being of organisms. Inappropriate cell survival and cell death decisions as well as cell competition between cells of different fitness are associated with many diseases such as cancer, autoimmune diseases and neurodegeneration. The Bergmann Lab has developed genetic models in Drosophila to identify mechanisms that control the decision between cell death and cell survival.
- Xu et al. (2005). The CARD-carrying caspase Dronc is essential for most, but not all, developmental cell death in Drosophila. Development 132, 2125-2134.
- Srivastava et al. (2007). ARK, the Apaf-1 related killer in Drosophila, requires diverse domains for its activity. Cell Death & Differentiation 14, 92-102.
- Lee et al. (2011). Drosophila IAP1-mediated ubiquitylation controls activation of the initiator caspase DRONC independently of protein degradation. PLoS Genetics 7(9) e1002261.
- Fan Y and Bergmann A (2014). Multiple mechanisms modulate distinct cellular susceptibilities towards apoptosis in the developing Drosophila eye. Developmental Cell 30, 48-60.
The Castilla lab has defined the role of oncogenic mutations, including leukemia fusion gene CBFB-MYH11 and NRas-G12D, in the disruption of survival and differentiation pathways in pre-leukemic hematopoietic cells. A major interest of the Castilla Lab is the identification of the components of apoptosis and proliferation targeted by driver mutations that govern oncogene addiction in acute myeloid leukemia.
- Kuo et al. (2006) Cbf beta-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia. Cancer Cell 2006, 9(1):57-68.
- Pullikan et al. (2012) Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling. Blood, 120(4):868-79.
- Xue et al (2014) NrasG12D oncoprotein inhibits apoptosis of preleukemic cells expressing Cbfβ-SMMHC via activation of MEK/ERK axis. Blood, 124(3):426-36.
Programmed cell death, through either apoptosis (self-killing) or autophagy (self-eating), is a critical aspect of both the genesis and treatment of cancer. The Green lab has used transcription-based approaches, such as expression profiling, to identify new genes and regulatory pathways that play a role in apoptosis and cancer. In conjunction with the RNAi Core, the lab has also developed methods to perform phenotype-based genetic screens for the identification of genes involved in cell survival and proliferation in mammalian cells. Together, the results of these studies have provided new insights into the mechanisms of programmed cell death and its importance in both normal and disease states.
- Devireddy et al. (2005) A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell, 123(7):1293-305.
- Sheng et al. (2011) BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription. Blood, 118(10):2840-8.
- Wang SZ et al. (2012) Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons. Proc Natl Acad Sci U S A. 109(45):18589-94.
Deterioration of mitochondria is a common component of numerous diseases as well as the aging process. The Haynes Lab focuses on mechanisms utilized by cells to maintain or recover mitochondrial activity and cellular health in a number of physiologic and pathologic scenarios focusing on a stress response known as the mitochondrial UPR.
- Nargund AN*, Pellegrino MW*, Fiorese CJ, Baker BM, Haynes CM. (2012) Mitochondrial import of ATFS-1 regulates mitochondrial UPR activation. Science. Aug 3;337(6094): 587-90.
- Fiorese CJ*, Schulz AM*, Lin YF, Rosin N, Pellegrino MW, Haynes CM. (2016) The transcription factor ATF5 mediates a mammalian mitochondrial UPR. Current Biology. 2016.
- Lin YF, Schulz AM, Pellegrino MW, Lu Y, Shaham S, Haynes CM. (2016) Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response. Nature. May 2:533(7603): 416-419.
- Lamech, LT, Haynes CM. (2015) The unpredictability of prolonged activation of stress response pathways. Journal of Cell Biology. June 22:209(6): 781-87.
Tissue homeostasis requires a careful balance between cellular proliferation, differentiation, and cell death. Research in the Kelliher Lab focuses on the role of RIP kinases and how they regulate cell death, particularly in the context of inflammation. For this purpose, they rely on the mouse as a model system to interrogate the pathways that control inflammation. In particular, the Kelliher Lab has developed conditional and kinase inactive knock-in alleles of RIPK1 that they have used to reveal novel physiologic requirements for RIPK1 in tissue homeostasis.
- Dannappel et al. (2014) RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature, 513(7516):90-4
- Roderick et al. Hematopoietic RIPK1 deficiency results in bone marrow failure caused by apoptosis and RIPK3-mediated necroptosis. (2014) Proc Natl Acad Sci U S A. 111(40):14436-41
The process of organ formation during embryonic development requires the precise integration of many different cellular outputs. Using the zebrafish as a model system, the Lawson Laboratory investigates how cells coordinate their behaviors during formation of the circulatory system. Through the application of in vivo time-lapse imaging, along with both forward and genetic approaches, the Lawson Lab has discovered new insights into how blood vessels form in the developing embryo.
Self-renewal, proliferation and differentiation of tissue-specific stem cells and progenitors are governed by several critical developmental signaling pathways, including the Hedgehog, Hippo and Wnt pathways. Dysregulation of these pathways leads to formation of a broad range of human cancers, including cancers arising from the gastrointestinal tract. The Mao laboratory uses a combination of cellular and mouse genetic approaches to understand the mechanism underlying these pathways in regulation of stem/progenitor cell function, tissue patterning, and their involvement in gastrointestinal tumorigenesis.
- Rajurkar et al. (2012) The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. PNAS. 109(17): E1038-47.
- Huang et al. (2013) Specific requirement of Gli transcription factors in Hedgehog-mediated intestinal development. J Biol Chem. 288(24):17589-96.
- Wang et al. (2013) TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBP function. Molecular Cell 51(2):211-25.
The Socolovsky lab has identified several anti-death signaling pathways that are coordinated by the erythropoietin receptor. Together these pathways are responsible for homeostasis and for the stress response in the erythropoietic system. For more information, see their website.
- Koulnis et al. (2012) Contrasting dynamic responses in vivo of the Bcl-xL and Bim erythropoietic survival pathways. Blood, 119(5):1228-39.
- Porpiglia et al. (2012) Stat5 signaling specifies basal versus stress erythropoietic responses through distinct binary and graded dynamic modalities. PLoS Biol. 2012 Aug;10(8):e1001383.
- Koulnis M et al. (2014) Erythropoiesis: from molecular pathways to system properties. Adv Exp Med Biol. 844:37-58.
Autophagy involves the enclosure of cytoplasmic material in the autophagosome and its subsequent delivery to the lysosome for degradation. Studies of autophagy in yeast have laid the groundwork for a molecular understanding of the autophagy pathway, but have failed to consider unique mechanisms that are specific for the regulation and function of autophagy in animals. The Zhang laboratory identified a set of metazoan specific autophagy genes, known as epg genes, using C. elegans as a genetic model. Research in the Zhang lab focuses on understanding the molecular mechanisms of these new genes in autophagy and how autophagy dysfunction leads to the development of neurodegeneration.
- Zhang, Y.X., et al. (2009) SEPA-1 mediates the specific recognition and degradation of P granule components by autophagy in C. elegans. Cell 136, 308-321.
- Tian, Y., et al. (2010) C. elegans screen identifies autophagy genes specific to multicellular organisms. Cell 141, 1042-1055.
- Lu, Q., et al. (2011) The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes. Developmental Cell 21, 343-357.
- Zhao, H.Y., et al. (2013) Mice deficient in Epg5 exhibit selective neuronal vulnerability to degeneration. The Journal of Cell Biology 200, 731-741.
- Li, S.H., et al. (2013) Arginine methylation modulates autophagic degradation of PGL granules in C. elegans. Molecular Cell 52, 421-433.
- Guo, B., et al. (2014) O-GlcNAc-modification of SNAP-29 regulates autophagosome maturation. Nature Cell Biology 16, 1215-1226.
- Wu, F., et al. (2015) Structural basis of the differential function of the two C. elegans Atg8 homologs, LGG-1 and LGG-2, in autophagy. Molecular Cell 60, 914-929.
- Wang, Z., et al. (2016) The Vici syndrome protein EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. Molecular Cell 63, 781-795.
- Zhao, G.Y., et al. (2017) The ER-localized transmembrane protein VMP1 regulates SERCA activity to control ER-isolation membrane contacts for autophagosome formation. Molecular Cell 67, 974-989.