S-phase arrest and apoptosis induced in normal mammary epithelial cells by a novel retinoid.
The addition of all-trans-retinoic acid has been found to mediate a G1 cell cycle phase arrest but not apoptosis in normal mammary epithelial cells. We have now found that addition of the novel retinoid 6-[3-(1-adamantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), which appears to function through a pathway independent of retinoic acid nuclear receptors, results in an S-phase arrest that is preceded by a 4-fold elevation in the levels of the cyclin-cyclin dependent kinase (cdk) inhibitor p21WAF1/CIP1. Failure to inhibit E2F-1 activation of genes through its phosphorylation by the cyclin cdk2 kinase has been shown to result in S-phase arrest and apoptosis in a number of cell types. Although exposure of the normal mammary cells to CD437 does not result in modulation of cyclin A or cdk2 levels, an increase in E2F-1 levels and a marked inhibition of cyclin A/cdk2 kinase activity are observed. Exposure to CD437 results in enhanced E2F-1 binding to its DNA consensus sequences and transcriptional activity during S phase. We hypothesize that this enhanced E2F-1 transcriptional activity results in S-phase arrest and subsequent apoptosis that has been observed in other systems.
Zhang
Y
Y
John D. Dingell VA Medical Center, Karmanos Cancer Institute, Detroit, Michigan 48201, USA.
Rishi
A K
AK
Dawson
M I
MI
Tschang
R
R
Farhana
L
L
Boyanapalli
M
M
Reichert
U
U
Shroot
B
B
Van Buren
E C
EC
Fontana
J A
JA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001940:Breast / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects; D014162:Transfection; D001616:beta-Galactosidase / Q000235:genetics; D000097768:Retinoic Acid Receptor gamma
D000970:Antineoplastic Agents; D018844:Cyclin-Dependent Kinases; D008156:Luciferases; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D001616:beta-Galactosidase; D000097768:Retinoic Acid Receptor gamma; C099555:CD 437; C000607071:RARA protein, human; C082925:retinoic acid receptor beta