Fludarabine-induced apoptosis of B chronic lymphocytic leukemia cells includes early cleavage of p27kip1 by caspases

被引:25
作者
Sanhes, L
Tang, R
Delmer, A
DeCaprio, JA
Ajchenbaum-Cymbalista, F
机构
[1] Hop Hotel Dieu, APHP, Dept Hematol, INSERM 9912,EA 1517, F-75004 Paris, France
[2] Dana Farber Canc Inst, Boston, MA 02115 USA
关键词
chronic lymphocytic leukemia; apoptosis; cyclin; caspase; p27kip1;
D O I
10.1038/sj.leu.2402895
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of growth arrested clonal B lymphocytes that undergo apoptosis when treated with fludarabine. To further explore the mechanism for the cell cycle arrest, we examined the expression and activity of cyclin-dependent kinases and inhibitors in primary B-CLL cells. We observed high levels of p27kip1, cyclin D2, cyclin E, cdk2, and cdk4 expression in freshly isolated B-CLL cells. Despite high levels of cyclins and cdks, little cdk2 or cdk4 activity was observed with p27kip1 in complex with cyclinD2/ cdk4 and cyclin E/cdk2. Remarkably, when B-CLL cells were treated in vitro with fludarabine, p27kip1 underwent caspase-specific degradation accompanied by an increase in cdk4 activity. We conclude that the G0/G1 arrest of B-CLL cells may protect against apoptosis and that the decrease in p27kip1 expression by caspase cleavage may be a key step in chemotherapy-induced apoptosis in B-CLL.
引用
收藏
页码:1104 / 1111
页数:8
相关论文
共 41 条
[1]   The retinoblastoma protein pathway in cell cycle control and cancer [J].
Bartek, J ;
Bartkova, J ;
Lukas, J .
EXPERIMENTAL CELL RESEARCH, 1997, 237 (01) :1-6
[2]   Involvement of CED-3/ICE proteases in the apoptosis of B-chronic lymphocytic leukemia cells [J].
Bellosillo, B ;
Dalmau, M ;
Colomer, D ;
Gil, J .
BLOOD, 1997, 89 (09) :3378-3384
[3]   Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27 [J].
Bouchard, C ;
Thieke, K ;
Maier, A ;
Saffrich, R ;
Hanley-Hyde, J ;
Ansorge, W ;
Reed, S ;
Sicinski, P ;
Bartek, J ;
Eilers, M .
EMBO JOURNAL, 1999, 18 (19) :5321-5333
[4]   Caspase-dependent cleavage of the retinoblastoma protein is an early step in neuronal apoptosis [J].
Boutillier, AL ;
Trinh, E ;
Loeffler, JP .
ONCOGENE, 2000, 19 (18) :2171-2178
[5]   B-cell chronic lymphocytic leukemia: A bird of a different feather [J].
Caligaris-Cappio, F ;
Hamblin, TJ .
JOURNAL OF CLINICAL ONCOLOGY, 1999, 17 (01) :399-408
[6]   Phosphorylation of the retinoblastoma-related protein p130 in growth-arrested cells [J].
Canhoto, AJ ;
Chestukhin, A ;
Litovchick, L ;
DeCaprio, JA .
ONCOGENE, 2000, 19 (44) :5116-5122
[7]   Protease activation is required for glucocorticoid-induced apoptosis in chronic lymphocytic leukemic lymphocytes [J].
Chandra, J ;
Gilbreath, J ;
Freireich, EJ ;
Kliche, KO ;
Andreeff, M ;
Keating, M ;
McConkey, DJ .
BLOOD, 1997, 90 (09) :3673-3681
[8]   Requirement of p27(Kip1) for restriction point control of the fibroblast cell cycle [J].
Coats, S ;
Flanagan, WM ;
Nourse, J ;
Roberts, JM .
SCIENCE, 1996, 272 (5263) :877-880
[9]   A recombinant adenovirus expressing p27(Kip1) induces cell cycle arrest and lass of cyclin-Cdk activity in human breast cancer cells [J].
Craig, C ;
Wersto, R ;
Kim, M ;
Ohri, E ;
Li, ZW ;
Katayose, D ;
Lee, SJ ;
Trepel, J ;
Cowan, K ;
Seth, P .
ONCOGENE, 1997, 14 (19) :2283-2289
[10]  
DELMER A, 1995, BRIT J HAEMATOL, V89, P798