TABLE 1.

Summary of Smad4 dependency of genes regulated by TGF-β in HaCaT cellsa

TGF-β target geneDescriptionRegulationb
Early (1 h) targets
    Smad4 dependent
        BMP2K BMP2-inducible kinaseUp
        CLU ClusterinUp
         DLX2 Distal-less homeo box 2Up
         GADD45B Growth arrest and DNA-damage-inducible, betaUp
        PRKD2 Protein kinase D2Up
        TGM4 Transglutaminase 4Up
         TIEG TGF-β-inducible early growth responseUp
        COPA Coatomer protein complex, subunit alphaDown
        LDLR Low-density lipoprotein receptorDown
    Smad4 independent
        CLC Cardiotrophin-like cytokineUp
        EDN1 Endothelin-1Up
        HES1 Hairy and enhancer of split 1.Up
        IER3 Immediate-early response 3Up
         SNAI2 (Slug) c Snail homolog 2Up
        MAIL Molecule possessing ankyrin repeatsDown
        TPD52 Tumor protein D52Down
Early (1 h) and late (6 h) targets
    Smad4 dependent
        AKT3 v-akt murine thymoma viral oncogene homolog 3Up
         ATF3 Activating transcription factor 3Up
         BHLHB2 Basic helix-loop-helix domain containing, class B2Up
        CXCL11 Chemokine (C-X-C motif) ligand 11Up
         NEDD9 (Hef1) Neural precursor developmentally down-regulated 9Up
         PAI1 c Plasminogen activator inhibitor type 1Up
        SERTAD4 SERTA domain containing 4Up
        TGM1 Transglutaminase 1Up
    Smad4 independent
         CDKN1A (p21) c Cyclin-dependent kinase inhibitor 1AUp
        c-JUN c v-jun sarcoma virus 17 oncogene homologUp
         JUNB junB proto-oncogeneUp
         MADH7 (Smad7) c MAD, mothers against decapentaplegic homolog 7Up
        PTHLH Parathyroid hormone-like hormoneUp
        RDC1 G protein-coupled receptorUp
         SKIL (sno) SKI-likeUp
         TCF8 Transcription factor 8Up
         TMEPAI c Transmembrane, prostate androgen-induced RNAUp
        VMP1 Likely ortholog of rat vacuote membrane protein 1Up
         CITED2 Cbp/p300-interacting transactivator 2Down
        RGS2 Regulator of G-protein signalling 2, 24 kDaDown
Late (6 h) targets
    Smad4 dependent
        AKAP12 c A kinase (PRKA) anchor protein (gravin) 12Up
        ARNTL Aryl hydrocarbon receptor nuclear translocator-likeUp
        BJ-TSA-9Hypothetical protein MGC14128Up
        CKLFSF3 Chemokine-like factor super family 3Up
        ETS2 v-ets erythroblastosis virus E26 oncogene homolog 2 (avian)Up
        IRAK2 Interleukin-1 receptor-associated kinase 2Up
         ITGB6 c Integrin, beta 6Up
        LAMC2 Laminin, gamma 2Up
        MASP2 Mannan-binding lectin serine protease 2Up
        PHACTR3 Phosphatase and actin regulator 3Up
        POLR2J2 DNA directed RNA polymerase II polypeptide J-related geneUp
         SMURF1 c E3 ubiquitin ligase SMURF1Up
        ZNF198 Zinc finger protein 198Up
        AMSH-LP Associated molecule with the SH3 domain of STAM-like proteinDown
        CLDN8 Claudin 8Down
        FLG FilaggrinDown
        FOXQ1 Forkhead box Q1Down
        GALNT5 UDP-N-acetyl-α-d-galactosamineDown
        GLMN Glomulin, FKBP-associated proteinDown
        GPR126 G protein-coupled receptor 126Down
        IL1RN Interleukin-1 receptor antagonistDown
        PARD6B Par-6 partitioning defective 6 homolog beta (Caenorhabditis elegans)Down
        PBX1 Pre-B-cell leukemia transcription factor 1Down
        PCDH7 BH-protocadherin 7 (brain-heart)Down
        PLEKHK1 Pteckstrin homology domain containing, family K member 1Down
        RAB27B RAB27B, member RAS oncogene familyDown
        RASSF5 Similar to protein interacting with GEFDown
        RDH10 Retinol dehydrogenase 10 (all-trans)Down
        TBX3 Transcription factor Tbx3Down
        TIMP3 Tissue inhibitor of metalloproteinase 3Down
        TNFSF10 Tumor necrosis factor (ligand) superfamily, member 10Down
        ZNF488 Zinc finger protein 488Down
    Smad4 independent
        ACTN1 Actinin, alpha 1Up
        ADAM19 A disintegrin and metalloproteinase domain 19Up
        AMIGO2 Amphoterin-induced gene 2Up
         CDKN2B (p15) c Cyclin-dependent kinase inhibitor 2BUp
        CHST11 Carbohydrate (chondroitin 4) sulfotransferase 11Up
         COL4A1 Collagen, type IV, alpha 1Up
        CST6 Cystatin E/MUp
        DLC1 Deleted in liver cancer 1Up
        ELK3 ELK3, ETS-domain protein (SRF accessory protein 2)Up
        FHL2 Four and a half LIM domains 2Up
         FSTL3 Follistatin-like 3Up
        HS3ST2 Heparan sulfate (glucosamine) 3-O-sulfotransferase 2Up
        IVL InvolucrinUp
        KAL1 Kallmann syndrome 1 sequenceUp
        LBH Likely ortholog of mouse limb-bud and heart geneUp
        LIPG Lipase, endothelialUp
        LTBP2 Latent transforming growth factor beta binding protein 2Up
        MGC29643 Hypothetical protein MGC29643Up
        NAV2 Neuron navigator 2Up
         NET1 Neuroepithelial cell transforming gene 1Up
        P114-RHO-GEF Rho-specific guanine nucleotide exchange factor p114Up
        PAPPA Pregnancy-associated plasma protein A, pappalysin 1Up
        PTGS2 Prostaglandin-endoperoxide synthase 2Up
        PTPRB Protein tyrosine phosphatase, receptor type, BUp
         RUNX1 Runt-related transcription factor 1Up
        SEC14L2 SEC14-like 2 (Saccharomyces cerevisiae)Up
        SEMA3C Sema domain, immunoglobulin domain (semaphorin) 3CUp
        SOX4 SRY (sex-determining region Y)-box 4Up
        TAGLN TransgelinUp
        TGFB2 TGF-β2Up
        TP73L Tumor protein p73-likeUp
        ANKRD22 Ankyrin repeat domain 22Down
        BCMP11 Breast cancer membrane protein 1Down
        CLDN1 Claudin 1Down
        CLECSF2 C-type lectin, superfamily member 2Down
        CYP1A1 Cytochrome P450, family 1A, polypeptide 1Down
        DOCK8 Dedicator of cytokinesis 8Down
        GATA3 GATA binding protein 3Down
        GBP2 Guanylate binding protein 2, interferon-inducibleDown
         ID2 Inhibitor of DNA binding 2Down
         ID3 Inhibitor of DNA binding 3Down
        ID4 Inhibitor of DNA binding 4Down
        IFIT2 Interferon-induced protein with tetratricopeptide repeats 2Down
        PPFIBP2 PTPRF-Interacting protein, binding protein 2 (liprin beta 2)Down
        SASH1 SAM and SH3 domain containing 1Down
        TGFBR3 TGF-β receptor IIIDown
  • a Transcription profiles were analyzed on Affymetrix U133A and B GeneChips, which correspond to about 33,000 well-substantiated human genes. A list of TGF-β-regulated genes was generated by selecting genes whose signal was increased (up) or decreased (down) by more than twofold in duplicate experiments after 1 h (early target genes) or 6 h (late target genes) of TGF-β treatment in the HaCaT-TR control cell line. Genes have been scored as Smad4 dependent or independent TGF-β targets as described in the Materials and Methods. Known TGF-β target gene products are represented in bold.

  • b Genes which are up-regulated or down-regulated by TGF-β are annotated “Up” or “Down,” respectively.

  • c Target genes for which regulation has been confirmed either by RT-PCR, RNase protection, or Western blot.