Highly integrative cellular processes-those involving many components with interactions distributed widely over time and space-are some of the most challenging and important in the basic biology of human disease. In this proposal, we discuss biochemical, biophysical and mathematical approaches to the physiology and molecular circuits underlying size control in somatic cells, and the pathways responsible for cell shape and polarity. Both types of processes are of importance in embryonic development, cancer, inflammation, and senescence, where morphogenesis, cell motility, growth and size control play prominent roles. Each of our approaches is based on a major technical innovation or conceptual development during the previous grant period. For cell size control, we have helped to develop three new methods for measuring growth at the individual cell level. We propose to use these methods for understanding size control and specifically, size homeostasis. One is a widely applicable computational method for extracting dynamic measurements of great accuracy from static observations of fixed cells. With it, we hope to learn how cells compensate by some feedback process for the naturally tendency of a population to increase its size variation. The other two methods make use of new technologies that can accurately weigh a human cell as it grows. For actin assembly, we have identified the conditions for activating the WAVE complex;we now plan to set up an in vitro system on supported lipid bilayers to assemble actin arrays, characteristic of lamellipodia, using this purified system or concentrated extracts and to test these mechanisms in embryonic frog cells. We have recently described a system for generating filopodia-like structures on such bilayers with cell extracts and defined lipids;we plan to understand the steps in assembling the filopodial tip complex. From such studies, we hope to learn how the biophysical properties of the known signaling and structural components of the membrane and actin system give rise to the characteristic structures in the cell. With increased understanding of size control and morphogenesis, we will be able to understand better the molecular circuits for growth, division, and metastasis, which are so important in cancer and increasingly important in cancer chemotherapy.
Most human diseases, such as cancer, inflammatory, and neurodegenerative diseases, are caused by disruptions of complex cellular or intercellular pathways that affect cell size and morphology. In this proposal, we offer new ways to measure the physiology of cell growth and to reconstitute pathways dictating cell shape and organization;our goal is to identify the molecular circuits underlying these processes and provide new bases for treatment. .
|Slenn, Tamara J; Morris, Benjamin; Havens, Courtney G et al. (2014) Thymine DNA glycosylase is a CRL4Cdt2 substrate. J Biol Chem 289:23043-55|
|Gujral, Taranjit Singh; Peshkin, Leonid; Kirschner, Marc W (2014) Exploiting polypharmacology for drug target deconvolution. Proc Natl Acad Sci U S A 111:5048-53|
|Li, Victor C; Kirschner, Marc W (2014) Molecular ties between the cell cycle and differentiation in embryonic stem cells. Proc Natl Acad Sci U S A 111:9503-8|
|Wang, Weiping; Wu, Tao; Kirschner, Marc W (2014) The master cell cycle regulator APC-Cdc20 regulates ciliary length and disassembly of the primary cilium. Elife 3:e03083|
|Ortiz-Meoz, Rodrigo F; Merbl, Yifat; Kirschner, Marc W et al. (2014) Microarray discovery of new OGT substrates: the medulloblastoma oncogene OTX2 is O-GlcNAcylated. J Am Chem Soc 136:4845-8|
|Xiong, Fengzhu; Ma, Wenzhe; Hiscock, Tom W et al. (2014) Interplay of cell shape and division orientation promotes robust morphogenesis of developing epithelia. Cell 159:415-27|
|Zhao, Rui; Deibler, Richard W; Lerou, Paul H et al. (2014) A nontranscriptional role for Oct4 in the regulation of mitotic entry. Proc Natl Acad Sci U S A 111:15768-73|
|Cooper, Kimberly L; Oh, Seungeun; Sung, Yongjin et al. (2013) Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions. Nature 495:375-8|
|Gallop, Jennifer L; Walrant, Astrid; Cantley, Lewis C et al. (2013) Phosphoinositides and membrane curvature switch the mode of actin polymerization via selective recruitment of toca-1 and Snx9. Proc Natl Acad Sci U S A 110:7193-8|
|Sung, Yongjin; Tzur, Amit; Oh, Seungeun et al. (2013) Size homeostasis in adherent cells studied by synthetic phase microscopy. Proc Natl Acad Sci U S A 110:16687-92|
Showing the most recent 10 out of 58 publications