Many cells, including some tumor cells, appear to secrete autocrine factors that repress their proliferation. In most cases the factors and associated signal transduction pathways are unknown. The PI has found that growing Dictyostelium cells secrete a protein called AprA for autocrine proliferation repressor. AprA is a 60 kDa protein, is part of a secreted approximately 150 kDa complex, and has some similarity to bacterial and mammalian proteins of unknown function. Compared to wild-type cells, aprA null cells proliferate faster while AprA overexpressing cells proliferate slower. Furthermore, adding immunoprecipitated AprA to cells slows their proliferation. I propose three specific aims to elucidate the mechanisms by which AprA regulates cell proliferation. First, we will determine if the approximately 150 kDa factor contains AprA alone or AprA plus additional factors, by purifying this factor and identifying its components. Second, we will determine if our candidate receptor for this factor senses and binds this factor, or is part of a different pathway that inhibits proliferation. Third, we will identify downstream components that are required for the growth inhibitory action of this factor. In preliminary screens, we identified four suppressors of the slow-proliferation AprA overexpressor phenotype; one encodes a protein with similarity to CLN2, a gene implicated in juvenile neuronal ceroid lipofuscinosis, poorly differentiated tumors, and cardiac hypertrophy. We will make nulls of suppressor genes and determine if they are part of the AprA signal transduction pathway, or are part of a different mechanism that represses proliferation. Our identification of the aprA mutant and AprA protein has opened the way for the application of molecular and genetic analysis to the mechanism by which extracellular factors can inhibit proliferation. We anticipate that these studies will assist in understanding both how normal tissue and tumor growth are regulated in multicellular organisms, and may help lead to novel ways to repress tumor cell proliferation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM074990-02
Application #
7220566
Study Section
Special Emphasis Panel (ZRG1-CSD-D (01))
Program Officer
Anderson, Richard A
Project Start
2006-05-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
2
Fiscal Year
2007
Total Cost
$278,841
Indirect Cost
Name
Rice University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005
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:
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
Herlihy, Sarah E; Tang, Yitai; Gomer, Richard H (2013) A Dictyostelium secreted factor requires a PTEN-like phosphatase to slow proliferation and induce chemorepulsion. PLoS One 8:e59365
Phillips, Jonathan E; Gomer, Richard H (2012) A secreted protein is an endogenous chemorepellant in Dictyostelium discoideum. Proc Natl Acad Sci U S A 109:10990-5
Phillips, Jonathan E; Huang, Eryong; Shaulsky, Gad et al. (2011) The putative bZIP transcription factor BzpN slows proliferation and functions in the regulation of cell density by autocrine signals in Dictyostelium. PLoS One 6:e21765
Gomer, Richard H; Jang, Wonhee; Brazill, Derrick (2011) Cell density sensing and size determination. Dev Growth Differ 53:482-94
Jang, Wonhee; Gomer, Richard H (2011) Initial cell type choice in Dictyostelium. Eukaryot Cell 10:150-5
Phillips, Jonathan E; Gomer, Richard H (2010) The ROCO kinase QkgA is necessary for proliferation inhibition by autocrine signals in Dictyostelium discoideum. Eukaryot Cell 9:1557-65
Bakthavatsalam, Deenadayalan; Gomer, Richard H (2010) The secreted proteome profile of developing Dictyostelium discoideum cells. Proteomics 10:2556-9

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