LAMIN PROTEOLYSIS FACILITATES NUCLEAR EVENTS DURING APOPTOSIS

Citation
L. Rao et al., LAMIN PROTEOLYSIS FACILITATES NUCLEAR EVENTS DURING APOPTOSIS, The Journal of cell biology, 135(6), 1996, pp. 1441-1455
Citations number
65
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell Biology
Journal title
ISSN journal
0021-9525
Volume
135
Issue
6
Year of publication
1996
Part
1
Pages
1441 - 1455
Database
ISI
SICI code
0021-9525(1996)135:6<1441:LPFNED>2.0.ZU;2-#
Abstract
Expression of the adenovirus E1A oncogene stimulates both cell prolife ration and p53-dependent apoptosis in rodent cells. p53 implements apo ptosis in all or in part through transcriptional activation of bax, th e product of which promotes cell death. The adenovirus E1B 19K product is homologous in sequence and in function to Bcl-2, both of which bin d to and inhibit the activity of Bar and thereby suppress apoptosis. T he E1B 19K protein also interacts with the nuclear lamins, but the rol e of this interaction in the regulation of apoptosis is not known. Lam ins are, however, substrates for members of the interleukin-1 beta-con verting enzyme (ICE) family of cysteine proteases that are activated d uring apoptosis and function downstream of Bcl-2 in the cell death pat hway. Lamins are degraded during E1A-induced p53-dependent apoptosis, Lamin A and C are cleaved into 47- and 37-kD fragments, respectively, and the site of proteolysis is mapped to a conserved aspartic acid res idue at position 230, The cleavage of lamins during apoptosis is consi stent with the activation of an ICE-related cysteine protease downstre am of p53. No lamin protease activity was detected in cells expressing the E1B 19K protein, indicating that 19K functions upstream of protea se activation in inhibiting apoptosis. Substitution of the aspartic ac id at the cleavage site produced a mutant lamin protein that was resis tant to proteolysis both in vitro and in vivo. Expression of uncleavab le mutant lamin A or B attenuated apoptosis, delaying cell death and t he associated DNA fragmentation by 12 h. Mutant lamin expressing cells failed to show the signs of chromatin condensation and nuclear shrink age typical of cell death by apoptosis. Instead, the nuclear envelope collapsed and the nuclear lamina remained intact. However, the late st age of apoptosis was morphologically unaltered and formation of apopto tic bodies was evident, Thus, lamin breakdown by proteolytic degradati on facilitates the nuclear events of apoptosis perhaps by facilitating nuclear breakdown.