A fundamental but poorly understood question in developmental biology is how cells stop proliferating when the density of cells of that cell type, n a tissue or the entire body, reaches the correct point. Theoretically, one way this can be accomplished is if the cells secrete a specific diffusible factor that inhibits proliferation of tht cell type. The extracellular concentration of such a factor, called a chalone, would increase as the density of the secreting cells increase, and when the density of that cell type reaches the correct point, the corresponding high levels of the chalone would stop their proliferation. Despite evidence for the existence of chalones, little is known about the identity of chalones and their signal transduction pathways. In the simple eukaryotic model system Dictyostelium discoideum, cells stop proliferating when they reach a high cell density even if adequate nutrients are presen+t. This is due to the extracellular accumulation of a chalone. We have partially purified the chalone and found that it is a heat- and protease-resistant anionic molecule smaller than 2 kDa. The chalone signal transduction pathway involves the PTEN and CnrN phosphatases and the BzpN transcription factor, and blocks proliferation by preventing the transition from the G2 to the M phase of the cell cycle. I propose three specific aims that will use the power of the Dictyostelium model system to elucidate this chalone and its signal transduction pathway. First, we will finish the purification and identify the chalone, and test theoretical models of chalone function. Second, we will test the hypothesis that the chalone regulates the PI3 kinase/ Akt pathway to regulate proliferation, and use genetic screens to identify additional components of the pathway. Third, we will test the hypothesis that the chalone blocks the cell cycle by inhibitin the activity of the G2/ M regulators Cyclin B and Cdc2. Together, this work combining natural products chemistry, physics and mathematical modeling, genetics, cell biology, and biochemistry in a versatile model system wil elucidate the molecular mechanism of a chalone.

Public Health Relevance

Some normal cells and some tumor cells appear to secrete unknown factors that inhibit their proliferation. If we could identify these factors, injecting the into a cancer patient might slow or stop the proliferation of the tumor. The proposed work will use a versatile model system to gain key insights into such factors and how they are sensed by cells, and could help to identify similar factors in humans.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Development - 1 Study Section (DEV1)
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Gaillard, Shawn R
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Texas A&M University
Schools of Arts and Sciences
College Station
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Tang, Yu; Wu, Yuantai; Herlihy, Sarah E et al. (2018) An Autocrine Proliferation Repressor Regulates Dictyostelium discoideum Proliferation and Chemorepulsion Using the G Protein-Coupled Receptor GrlH. MBio 9:
Herlihy, Sarah E; Tang, Yu; Phillips, Jonathan E et al. (2017) Functional similarities between the dictyostelium protein AprA and the human protein dipeptidyl-peptidase IV. Protein Sci 26:578-585
Suess, Patrick M; Watson, Jacob; Chen, Wensheng et al. (2017) Extracellular polyphosphate signals through Ras and Akt to prime Dictyostelium discoideum cells for development. J Cell Sci 130:2394-2404
Suess, Patrick M; Gomer, Richard H (2016) Extracellular Polyphosphate Inhibits Proliferation in an Autocrine Negative Feedback Loop in Dictyostelium discoideum. J Biol Chem 291:20260-9
Herlihy, Sarah E; Brown, Monica L; Pilling, Darrell et al. (2015) Role of the neutrophil chemorepellent soluble dipeptidyl peptidase IV in decreasing inflammation in a murine model of arthritis. Arthritis Rheumatol 67:2634-8
Phillips, Jonathan E; Gomer, Richard H (2015) Partial genetic suppression of a loss-of-function mutant of the neuronal ceroid lipofuscinosis-associated protease TPP1 in Dictyostelium discoideum. Dis Model Mech 8:147-56
Phillips, Jonathan E; Gomer, Richard H (2014) The p21-activated kinase (PAK) family member PakD is required for chemorepulsion and proliferation inhibition by autocrine signals in Dictyostelium discoideum. PLoS One 9:e96633
Bakthavatsalam, Deenadayalan; White, Michael J V; Herlihy, Sarah E et al. (2014) A retinoblastoma orthologue is required for the sensing of a chalone in Dictyostelium discoideum. Eukaryot Cell 13:376-82
DeBord, John Daniel; Smith, Donald F; Anderton, Christopher R et al. (2014) Secondary ion mass spectrometry imaging of Dictyostelium discoideum aggregation streams. PLoS One 9:e99319
Herlihy, Sarah E; Pilling, Darrell; Maharjan, Anu S et al. (2013) Dipeptidyl peptidase IV is a human and murine neutrophil chemorepellent. J Immunol 190:6468-77

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