The 43000 growth-associated protein functions as a negative growth regulator in glioma.
Previous molecular analyses of human astrocytomas have identified many genetic changes associated with astrocytoma formation and progression. In an effort to identify novel gene expression changes associated with astrocytoma formation, which might reveal new potential targets for glioma therapeutic drug design, we used the B8-RAS-transgenic mouse astrocytoma model. Using multiplex gene expression profiling, we found that growth-associated protein 43 (GAP43) RNA and protein expression were lost in select human and mouse glioma cell lines. In this study, we demonstrate that re-expression of GAP43 in deficient C6 glioma cells results in growth suppression in clonogenic assays, as well as in multiple independently derived C6 glioma cell lines in vitro. GAP43-expressing C6 cells also exhibit reduced tumor growth as s.c. explants in immunocompromised mice in vivo. In addition, GAP43-expressing C6 clones demonstrate impaired cell motility and increased homophilic aggregation. GAP43 re-expression is also associated with reduced mitogen-activated protein kinase and AKT activation in C6 cells, suggesting that GAP43 functions as a novel glioma growth suppressor by modulating mitogenic signaling pathways.
Huang
Zhi-Yong
ZY
Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Wu
YanLi
Y
Burke
Stephen P
SP
Gutmann
David H
DH
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002645:Chickens; D019922:GAP-43 Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D014162:Transfection; D014407:Tumor Cells, Cultured; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D019922:GAP-43 Protein; D006131:Growth Inhibitors; D011518:Proto-Oncogene Proteins; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020827:rap1 GTP-Binding Proteins