Blocking Chk1 expression induces apoptosis and abrogates the G2 checkpoint mechanism.
Checkpoint kinase 1 (Chk1) is a checkpoint gene that is activated after DNA damage. It phosphorylates and inactivates the Cdc2 activating phosphatase Cdc25C. This in turn inactivates Cdc2, which leads to G2/M arrest. We report that blocking Chk1 expression by antisense or ribozymes in mammalian cells induces apoptosis and interferes with the G2/M arrest induced by adriamycin. The Chk1 inhibitor UCN-01 also blocks the G2 arrest after DNA damage and renders cells more susceptible to adriamycin. These results indicate that Chk1 is an essential gene for the checkpoint mechanism during normal cell proliferation as well as in the DNA damage response.
Luo
Y
Y
Department 47S AP9A, Cancer Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. yan.luo@abbott.com
Rockow-Magnone
S K
SK
Kroeger
P E
PE
Frost
L
L
Chen
Z
Z
Han
E K
EK
Ng
S C
SC
Simmer
R L
RL
Giranda
V L
VL
D000470:Alkaloids / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004396:Coloring Agents; D017931:DNA Primers / Q000737:chemistry; D016373:DNA, Antisense / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D016195:G2 Phase / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008938:Mitosis; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D016337:RNA, Catalytic / Q000494:pharmacology; D019311:Staurosporine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D014966:Xanthenes
D000470:Alkaloids; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D017931:DNA Primers; D016373:DNA, Antisense; D004791:Enzyme Inhibitors; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D016337:RNA, Catalytic; D014966:Xanthenes; C005843:resazurin; D005047:Etoposide; C054852:7-hydroxystaurosporine; D004317:Doxorubicin; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D020169:Caspases; D019311:Staurosporine