Does p16ink4a expression increase with the number of cell doublings in normal and malignant lymphocytes?
p16(ink4a) is known to be a major inhibitor of cyclin-dependent kinases of G1-phase. Its accumulation is associated with replicative senescence. We analyzed to what extent the number of cell doublings may participate to p16(ink4a) expression in normal and malignant lymphocytes. p16(ink4a) expression, not found in normal quiescent B or T-lymphocytes, was observed after stimulation of B-lymphocytes (72 h) and T-lymphocytes (2 weeks) before the occurrence of replicative senescence markers such as senescence-associated-beta-galactosidase activity. Afterwards, in lymphocyte long-term cultures, the increase in p16(ink4a) followed the expression of features of cell ageing. In acute lymphoblastic leukemia, the analysis of the individual differences between peripheral blood and blood compartments (34 cases) showed a decrease in cell proliferation (p<0.005), in telomerase activity (p<0.0005), and in hTERT expression (p<0.04), associated with an increase of p16(ink4a) (p<0.035) in blood leukemic cells. These results support the hypothesis that (i) an increase in p16(ink4a) expression in normal lymphocytes is linked, in part, to the number of cell doublings before the occurrence of replicative senescence and (ii) this process is maintained in leukemic cell populations of numerous patients.
Chebel
Amel
A
Université Lyon1, Equipe d'Accueil 3737, Faculté Lyon-Sud, Oullins, France.
Chien
Wei-Wen
WW
Gerland
Luc-Marie
LM
Mekki
Yahia
Y
Bertrand
Yves
Y
Ffrench
Patrick
P
Galmarini
Carlos Maria
CM
Ffrench
Martine
M
D000293:Adolescent; D002455:Cell Division; D049109:Cell Proliferation; D016922:Cellular Senescence; D002648:Child; D002675:Child, Preschool; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007223:Infant; D008214:Lymphocytes / Q000166:cytology*; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; C509186:TERT protein, human; D019098:Telomerase