ING1b decreases cell proliferation through p53-dependent and -independent mechanisms.
ING1b can stimulate cell cycle arrest, repair, senescence, and apoptosis. The actions of ING1b are attributed to its activation of the tumor suppressor p53. Here we investigate the more subtle effects of ING1b on the cell cycle and DNA damage responses in the absence of p53. To this end, we have generated isogenic cell lines that expressed ING1b and p53 either individually or in combination under the control of inducible promoters. A five- to 10-fold induction of ING1b over the endogenous protein in a p53-null H1299 background slightly impairs proliferation by increasing the doubling time by approximately 10%. Significantly, ectopic expression of ING1b enhanced the G(2)/M DNA damage checkpoint induced by adriamycin. We demonstrated that the DNA damage-induced cell death mediated by the cooperation between ING1b and p53 was more prominent than by the individual proteins alone. In adriamycin-treated cells, p53 was stabilized and induced the expression of p21(CIP1/WAF1), but the expression of ING1b was not affected. The exact targets of ING1b in the p53-null background are not known, but we demonstrated that the transcriptional activities of other members of the p53 family, p63alpha and p73alpha, could be activated by ING1b. These data indicate that ING1 has a subtle antiproliferative effect even in the absence of p53, and ING1b enhances the DNA damage responses through p53-dependent and -independent mechanisms.
Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Fan Cheung
FC
Tsang
Lai See
LS
Po
Ka Man
KM
Leung
Anita
A
Lau
Wai Yi
WY
Siu
Randy Y C
RY
Poon
D018797:Cell Cycle Proteins; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000502:physiology; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; C081876:CKAP4 protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D010750:Phosphoproteins; D011506:Proteins; D011994:Recombinant Proteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D014404:Tubulin; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin