Functional role of cyclin A on induction of fibroblast apoptosis due to ligation of CD44 matrix receptor by anti-CD44 antibody

Ligation of cell surface matrix adhesion receptors such as integrins can in crease expression of specific cell cycle regulatory proteins such as cyclin A, thereby regulating cell cycle progression. Disruption of cell surface m atrix receptor interaction with the extracellular matrix can trigger apopto sis. Induction of apoptosis has been linked to unscheduled up-regulation of cyclin A and activation of cyclin-A-associated dependent kinase 2 activity due to cleavage of cyclin-dependent kinase inhibitors by caspases. We have found that ligation of the cell surface matrix adhesion receptor CD44 by a nti-CD44 antibody induces cell detachment and triggers apoptosis, In this r eport we show that ligation of CD44 by anti-CD44 antibody increases the exp ression of cyclin A protein prior to activation of caspase-3-like activity and morphological changes of apoptosis. Down-regulation of cyclin A protein levels by cyclin A antisense oligonucleotides dramatically decreased fibro blast apoptosis in response to anti-CD44 antibody. These data identify an i mportant functional role of cyclin A in the induction of fibroblast apoptos is due to the ligation of the cell surface adhesion receptor CD44 by anti-C D44 antibody. (C) 2000 Academic Press.