Retinoic acid induces TGFbeta-dependent autocrine fibroblast growth.
To evaluate the role of murine TFIID subunit TAF4 in activation of cellular genes by all-trans retinoic acid (T-RA), we have characterized the T-RA response of taf4(lox/-) and taf4(-/-) embryonic fibroblasts. T-RA regulates almost 1000 genes in taf4(lox/-) cells, but less than 300 in taf4(-/-) cells showing that TAF4 is required for T-RA regulation of most, but not all cellular genes. We further show that T-RA-treated taf4(lox/-) cells exhibit transforming growth factor (TGF)beta-dependent autocrine growth and identify a set of genes regulated by loss of TAF4 and by T-RA corresponding to key mediators of the TGFbeta signalling pathway. T-RA rapidly and potently induces expression of connective tissue growth factor (CTGF) via a conserved DR2 type response element in its proximal promoter leading to serum-free autocrine growth. These results highlight the role of TAF4 as a cofactor in the cellular response to T-RA and identify the genetic programme of a novel cross talk between the T-RA and TGFbeta pathways that leads to deregulated cell growth.
Fadloun
A
A
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP. UMR7104, 1 Rue Laurent Fries, Illkirch Cédex, France.
Kobi
D
D
Delacroix
L
L
Dembélé
D
D
Michel
I
I
Lardenois
A
A
Tisserand
J
J
Losson
R
R
Mengus
G
G
Davidson
I
I
D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects* / Q000235:genetics; D001483:Base Sequence; D019556:COS Cells; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D055513:Connective Tissue Growth Factor; D016384:Consensus Sequence; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D020239:Receptor Cross-Talk / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D020218:Response Elements; D035362:Transcription Factor TFIID / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*; D000097768:Retinoic Acid Receptor gamma
D055513:Connective Tissue Growth Factor; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D018168:Receptors, Retinoic Acid; D035362:Transcription Factor TFIID; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C526318:CCN2 protein, mouse; C523528:TAF4 protein, mouse