The life (and death) of cells

Our lab studies how autophagy (self eating) is regulated and functions in complex multi-cellular organisms.  Autophagy is used to clear materials from cells, and helps to maintain cell health.  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. 2007 Dec 14;131(6):1137-48. PubMed PMID: 18083103; PubMed Central PMCID: PMC2180345.
• McPhee CK, Logan MA, Freeman MR, Baehrecke EH. Activation of autophagy during cell death requires the engulfment receptor Draper. Nature. 2010 Jun 24;465(7301):1093-6. PubMed PMID: 20577216; PubMed Central PMCID: PMC2892814.
• Chang TK, Shravage BV, Hayes SD, Powers CM, Simin RT, Wade Harper J, Baehrecke EH. Uba1 functions in Atg7- and Atg3-independent autophagy. Nat Cell Biol. 2013 Sep;15(9):1067-78. PubMed PMID: 23873149; PubMed Central PMCID: PMC3762904.
• Nelson C, Ambros V, Baehrecke EH. miR-14 regulates autophagy during developmental cell death by targeting ip3-kinase 2. Mol Cell. 2014 Nov 6;56(3):376-88. PubMed PMID: 25306920; PubMed Central PMCID: PMC4252298.
• Lin L, Rodrigues FSLM, Kary C, Contet A, Logan M, Baxter R, Wood W and Baehrecke EH (2017) Complement-related regulates autophagy in neighboring cells. Cell 2017 Jun 29;170(1):158-171. PMID: 2866617 PubMed Central PMCID: PMC5533186.
• Velentzas PD, Zhang L, Das G, Chang TK, Nelson C, Kobertz WR, Baehrecke EH. The proton-coupled monocarboxylate transporter Hermes is necessary for autophagy during cell death. Dev Cell. 2018 Oct 9: 47:281-293. PMID: 30318245 PubMed Central PMCID: in progress.

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.

• Benanti et al. (2007) A proteomic screen reveals SCF(Grr1) targets that regulate the glycolytic-gluconeogenic switch. Nature Cell Biology 9(10):1148-1191.
• Landry et al. (2012) F-box protein specificity for G1 cyclins is dictated by subcellular localization. PLoS Genetics 8(7): e1002851.

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.

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.

• Siekmann AF and Lawson ND. (2007) Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries.  Nature, 445(7129):781-4. 
• Nicoli et al.  (2010) MicroRNA-mediated integration of haemodynamics and Vegf signaling during angiogenesis.  Nature, 22;464(7292):1196-200. 

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.