Transcriptional Activation of the cdc2 Gene Is Associated with Fas-induced Apoptosis of Human Hematopoietic Cells

doi:10.1074/jbc.271.45.28469

Transcriptional Activation of the cdc2 Gene Is Associated with Fas-induced Apoptosis of Human Hematopoietic Cells*

From the Division of Hemopoiesis, Institute of Hematology, and the Department of Hematology, Jichi Medical School, Tochigi 329-04, Japan,
^§ Katsuta Research Laboratory, Hitachi Koki Co., Ltd., Ibaraki 312, Japan, and
^¶ Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd., Ibaraki 300-33, Japan

^‡ To whom all correspondence should be addressed:
Division of Hemopoiesis, Institute of Hematology, Jichi Medical School, Minamikawachi-machi, Kawachi-gun, Tochigi 329-04, Japan
. Tel: +81-285-44-2111; Fax: +81-285-44-1317.

Abstract

Apoptosis has recently been hypothesized to be the result of aberrant cell cycle control. In this study, we have investigated the role of cell cycle-regulatory elements in Fas-induced apoptosis of hematopoietic cells. When HL-60 cells were treated with anti-Fas antibody, rapid activation of growth-associated histone H1 kinase was observed without any change in cell cycle distribution. This was accompanied by the increase in cdc2 mRNA expression and Cdc2 kinase activity. Up-regulation of cdc2 mRNA was similarly induced in BCL-2-overexpressing HL-60 subline by anti-Fas treatment independently of the appearance of apoptotic phenotypes. Fas-induced apoptosis was completely inhibited by butyrolactone I, a specific inhibitor of Cdc2 kinase. Moreover, the same phenomenon was observed during Fas-induced but not spontaneous apoptosis of postmitotic granulocytes. Finally, we have found that “Fas-responsive element” was located between nucleotides −730 and −552 of the cdc2 promoter and was responsive for transcriptional activation of the cdc2 gene during Fas-induced apoptosis. These results indicate that aberrant activation of Cdc2 is associated with Fas-induced apoptosis of hematopoietic cells, and that the mechanism of cdc2 transcription during Fas-induced apoptosis is different from that in normal cell cycle control.

Footnotes

↵* This work was supported in part by a grant-in-aid from the Ministry of Education Science and Culture of Japan and by a grant from the Yamanouchi Foundation for Research on Metabolic Disorders (to Y. F.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

IFN

interferon

FBS

fetal bovine serum

PCR

polymerase chain reaction

GAPDH

glyceraldehyde-3-phosphate dehydrogenase

CAT

chloramphenicol acetyltransferase

CDK

cyclin-dependent kinase

RT-PCR

reverse-transcription PCR

nt

nucleotide(s).
- Received January 29, 1996.
- Revision received June 14, 1996.