The expression of novH in adrenocortical cells is down-regulated by TGFbeta 1 through c-Jun in a Smad-independent manner.
The human NOV secreted glycoprotein (NOVH) is abundant in the fetal and adult adrenal cortex. The amount of NOVH increases in benign adrenocortical tumors and decreases in malignant adrenocortical tumors, suggesting that NOVH plays a role in tumorigenesis in the adrenal cortex. Transforming growth factor beta1 (TGFbeta1), fibroblast growth factor 2 (FGF2), and insulin growth factors (IGFs) play crucial roles in the physiology of the adrenal cortex. We investigated the effects of these factors on the expression of novH in the NCI H295R adrenocortical cell line. The amounts of NOVH protein and novH transcripts were down-regulated by TGFbeta1 and up-regulated by FGF2, whereas IGFs had no effect. Furthermore, the TGFbeta1-dependent inhibition of novH promoter activity was completely abrogated following site-directed mutation of two activating protein (AP-1) sequences (positions -473 and -447), whereas the stimulatory effect of FGF2 was not affected. Co-transfection with dominant negative forms of c-Jun and MEKK1 also abrogated novH-targeted regulation by TGFbeta1, whereas the overproduction of Smad proteins or dominant negative forms of Smad had no effect. Taken together, these results suggest that c-Jun and MEKK1 signaling but not Smad signaling are involved in the TGFbeta1-dependent decrease in NOVH in NCI H295R cells. In conclusion, our data provide evidence that novH is a new target of TGFbeta1; unlike other members of the CCN (cyr61, ctgf, nov) family, however, its expression is repressed rather than induced.
Lafont
Jérôme
J
INSERM U515 and INSERM U482, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.
Laurent
Maryvonne
M
Thibout
Hélène
H
Lallemand
François
F
Le Bouc
Yves
Y
Atfi
Azeddine
A
Martinerie
Cécile
C
D000302:Adrenal Cortex / Q000166:cytology / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D055513:Connective Tissue Growth Factor; D004247:DNA; D015536:Down-Regulation / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D017874:Immediate-Early Proteins / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D055514:Nephroblastoma Overexpressed Protein; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012689:Sequence Homology, Nucleic Acid; D016212:Transforming Growth Factor beta / Q000502:physiology*; D015854:Up-Regulation
C526317:CCN2 protein, human; C526319:CCN3 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055514:Nephroblastoma Overexpressed Protein; D016755:Proto-Oncogene Proteins c-jun; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D055513:Connective Tissue Growth Factor; D004247:DNA