Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway.
Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). Expression of six of them (PINK1, EGR2, HCLS1, DUSP1, BPOZ, and NFIL3) was decreased in ovarian tumors compared with corresponding normal tissues. Colony-formation assays using plasmid clones designed to express each gene indicated that EGR2 and BPOZ were able to suppress growth of cancer cells significantly; in particular, cancer-cell lines stably expressing BPOZ grew more slowly than control cells containing mock vector. Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G(1)/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated. Therefore both genes appear to be novel candidates as mediators of the PTEN growth-suppressive signaling pathway.
Unoki
M
M
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
Nakamura
Y
Y
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000328:Adult; D000595:Amino Acid Sequence; D017089:Ankyrin Repeat; D050976:Basic-Leucine Zipper Transcription Factors; D001798:Blood Proteins / Q000235:genetics / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D002455:Cell Division / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D054638:Dual Specificity Phosphatase 1; D051767:Early Growth Response Protein 2; D020224:Expressed Sequence Tags; D005260:Female; D051790:G-Box Binding Factors; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D051059:PTEN Phosphohydrolase; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology; D054645:Protein Phosphatase 1; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012326:RNA Splicing; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins; D016415:Sequence Alignment; D015398:Signal Transduction / Q000235:genetics*; D013347:Subcellular Fractions / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein; D000099202:PTEN-Induced Putative Kinase
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D050976:Basic-Leucine Zipper Transcription Factors; D001798:Blood Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D054638:Dual Specificity Phosphatase 1; D051767:Early Growth Response Protein 2; D051790:G-Box Binding Factors; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D051059:PTEN Phosphohydrolase; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; D011494:Protein Kinases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D011506:Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein; D000099202:PTEN-Induced Putative Kinase; C402243:ABTB1 protein, human; C497326:EGR2 protein, human; C061909:HCLS1 protein, human; C497440:NFIL3 protein, human; C107249:SH2B2 protein, human; C517019:DUSP1 protein, human; C494929:PTEN protein, human