Dose-dependent activation of p21WAF1 transcription by all-trans-acid in cervical squamous carcinoma cells.
SiHa cervical squamous carcinoma cells were resistant to ATRA-induced growth inhibitory effect at a physiological dose (10(-6) M), but responsive at a pharmacological dose (10(-4) M). The observed growth arrest was associated with increased levels of the interferon regulatory factor-1 (IRF-1). IRF-1 is a known inhibitor of cell growth, and thus our aim was to identify the downstream target of this growth inhibitory function. We found that, as with the induction of IRF-1, levels of p21WAF1 were similarly dose-dependently induced by ATRA. Semiquantitative RT-PCR, Western blotting, gel-shift analysis (EMSA), antisense gene expression and application of a STAT1-knockout cell line demonstrated that activation of the p21WAF1 gene was IRF-1 and STAT1-dependent. We concluded that activation of STAT1 and IRF-1 is crucial for the growth inhibitory action of ATRA, which is associated with the activation of p21WAF1. These results might be useful in chemoprevention of cervical cancers.
Arany
Istvan
I
Department of Microbiology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA. AranyIstvan@uams.edu
Whitehead
William E
WE
Ember
Istvan A
IA
Tyring
Stephen K
SK
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D050856:Interferon Regulatory Factor-1; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016376:Oligonucleotides, Antisense; D010750:Phosphoproteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014212:Tretinoin