p75NTR enhances PC12 cell tumor growth by a non-receptor mechanism involving downregulation of cyclin D2.
p75NTR is a member of the tumor necrosis superfamily of proteins which is variably associated with induction of apoptosis and proliferation. Cyclin D2 is one of the mediators of cellular progression through G1 phase of the cell cycle. The present study demonstrates the inverse relationship between expression of cyclin D2 and expression of p75NTR in PC12 cells. Induction of p75NTR expression in p75NTR-negative PC12 cells results in downregulation of cyclin D2; suppression of p75NTR expression with siRNA in native PC12 cells results in upregulation of cyclin D2. The effects of p75NTR on cyclin D2 expression are mimicked in p75NTR-negative cells by transfection with the intracellular domain of p75NTR. Cyclin-D2-positive PC12 cell cultures grow more slowly than cyclin-D2-negative cultures, and induction of expression of cyclin D2 slows the culture growth rate of cyclin-D2-negative cells. Finally, subcutaneous murine xenografts of cyclin-D2-negative, p75NTR-positive PC12 cells more frequently and more rapidly produce tumors than the analogous xenografts of cyclin-D2-positive, p75NTR-negative cells. These results suggest that p75NTR suppresses cyclin D2 expression in PC12 cells by a mechanism distinct from its function as a nerve growth factor receptor and that cyclin D2 expression decreases cell culture and xenografted tumor growth.
Fritz
Melinda D
MD
Department of Pediatrics, University of Pittsburgh, PA, USA.
Mirnics
Zeljka K
ZK
Nylander
Karen D
KD
Schor
Nina F
NF
D000818:Animals; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism*; D015536:Down-Regulation; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D016716:PC12 Cells; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014183:Transplantation, Heterologous
C486197:Ccnd2 protein, rat; D056742:Cyclin D2; D016213:Cyclins; D034741:RNA, Small Interfering; D020800:Receptor, Nerve Growth Factor