Staurosporine-induced apoptosis is independent of p16 and p21 and achieved via arrest at G2/M and at G1 in U251MG human glioma cell line.
OBJECTIVE
The mechanisms involved in the cell cycle and cell death remain unresolved despite much investigation. Staurosporine induces cell death and G1 or G2/M arrest in a dose-dependent manner, but the mechanisms remain unknown.


METHODS
In the present study an adenovirus vector expressing p16 or p21 genes in human glioma cell lines was used to examine cell cycle regulation and cell death induced by staurosporine.


RESULTS
A low concentration (</=10 n M) of staurosporine induced G1 arrest of U251MG cells, whereas a high concentration (>/=30 n M) induced G2/M arrest and finally induced apoptosis via a caspase-3-activated pathway from both the G2/M and G1 phases. However, pRb was dephosphorylated and cdc2 was inhibited at both the low and the high concentrations of staurosporine, indicating that the mechanisms of cell cycle regulation are not simply p53-Rb- or cdc2-dependent pathways.


CONCLUSIONS
Forced G1 arrest by transfection with p16 or p21 genes did not alter the rate of staurosporine-induced cell death. This implies that an unknown pathway of apoptosis occurs from the G1 phase.
Yamasaki
Fumiyuki
F
Department of Neurosurgery, Faculty of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan. fyama@hiroshima-u.ac.jp
Hama
Seiji
S
Yoshioka
Hiroyuki
H
Kajiwara
Yoshinori
Y
Yahara
Kaita
K
Sugiyama
Kazuhiko
K
Heike
Yuji
Y
Arita
Kazunori
K
Kurisu
Kaoru
K
D000256:Adenoviridae; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D019311:Staurosporine / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D016203:CDC2 Protein Kinase; D019311:Staurosporine