TY - JOUR
T1 - Dissociation of bone morphogenetic protein-mediated growth arrest and apoptosis of mouse B cells by HPV-16 E6/E7
AU - Yamato, Kenji
AU - Hashimoto, Shinichi
AU - Okahashi, Nobuo
AU - Ishisaki, Akira
AU - Nonaka, Koji
AU - Koseki, Takeyoshi
AU - Kizaki, Masahiro
AU - Ikeda, Yasuo
AU - Nishihara, Tatsuji
N1 - Funding Information:
This work was supported in part by grants-in-aid from the Ministry of Education, Science, and Culture of Japan and from the Ministry of Health and Welfare of Japan.
PY - 2000/5/25
Y1 - 2000/5/25
N2 - We have previously found that bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-β family, induces cell-cycle arrest in the G1 phase and apoptotic cell death of HS-72 mouse hybridoma cells. In this study, we show that BMP-2 did not alter expression of cyclin D, cyclin E, cyclin-dependent kinase 2 (CDK2), CDK4, p27(KIP1) p16(INK4a), or p15(INK1b), but enhanced expression of p21(CIP1/WAF1). Accumulation of p21(CIP1/WAF1) resulted in increased binding of p21(CIP1/WAF1) to CDK4 and concomitantly caused a profound decrease in the in vitro retinoblastoma protein (Rb) kinase activity of CDK4. Furthermore, the ectopic expression of human papilloma virus type-16 E7, an inhibitor of p21(CIP1/waf1) and Rb, reverted G1 arrest induced by BMP-2. Expression of E6/E7, without increasing the p53 level, blocked inhibition of Rb phosphorylation and G1 arrest, but did not attenuate cell death in BMP-treated HS-72 cells. Taken together, these results suggest that inhibition of Rb phosphorylation by p21(CIP1/WAF1) is responsible for BMP-2-mediated G1 arrest and that BMP-2-induction of apoptosis might be independent of Rb hypophosphorylation. (C) 2000 Academic Press.
AB - We have previously found that bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-β family, induces cell-cycle arrest in the G1 phase and apoptotic cell death of HS-72 mouse hybridoma cells. In this study, we show that BMP-2 did not alter expression of cyclin D, cyclin E, cyclin-dependent kinase 2 (CDK2), CDK4, p27(KIP1) p16(INK4a), or p15(INK1b), but enhanced expression of p21(CIP1/WAF1). Accumulation of p21(CIP1/WAF1) resulted in increased binding of p21(CIP1/WAF1) to CDK4 and concomitantly caused a profound decrease in the in vitro retinoblastoma protein (Rb) kinase activity of CDK4. Furthermore, the ectopic expression of human papilloma virus type-16 E7, an inhibitor of p21(CIP1/waf1) and Rb, reverted G1 arrest induced by BMP-2. Expression of E6/E7, without increasing the p53 level, blocked inhibition of Rb phosphorylation and G1 arrest, but did not attenuate cell death in BMP-treated HS-72 cells. Taken together, these results suggest that inhibition of Rb phosphorylation by p21(CIP1/WAF1) is responsible for BMP-2-mediated G1 arrest and that BMP-2-induction of apoptosis might be independent of Rb hypophosphorylation. (C) 2000 Academic Press.
KW - Apoptosis
KW - BMP
KW - E6/E7
KW - G1 arrest
KW - HPV-16 E7
KW - P21(CIP1/WAF1)
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U2 - 10.1006/excr.2000.4876
DO - 10.1006/excr.2000.4876
M3 - Article
C2 - 10854068
AN - SCOPUS:0034713344
SN - 0014-4827
VL - 257
SP - 198
EP - 205
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 1
ER -