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J. Biol. Chem., Vol. 277, Issue 42, 39515-39524, October 18, 2002

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Differential, Tissue-specific, Transcriptional Regulation of Apolipoprotein B Secretion by Transforming Growth Factor ^*

Karnail Singh, Olcay A. Batuman^§, Hassan O. Akman, Mamdouh H. Kedees, Varsha Vakil, and M. Mahmood Hussain^¶

From the Departments of  Anatomy and Cell Biology, ^§ Medicine, and ^¶ Pediatrics, SUNY Downstate Medical Center, Brooklyn, New York 11203

Apolipoprotein B (apoB) is required for the assembly and secretion of triglyceride-rich lipoproteins. ApoB synthesis is constitutive, and post-translational mechanisms modulate its secretion. Transforming growth factor  (TGF-) increased apoB secretion in both differentiated and nondifferentiated Caco-2 cells and decreased secretion in HepG2 cells without affecting apolipoprotein A-I secretion. TGF- altered apoB secretion by changing steady-state mRNA levels and protein synthesis. Expression of SMAD3 and SMAD4 differentially regulated apoB secretion in these cells. Thus, SMADs mediate dissimilar secretion of apoB in both the cell lines by affecting gene transcription. We identified a 485-bp element, 55 kb upstream of the apob gene that contains a SMAD binding motif. This motif increased the expression of chloramphenicol acetyltransferase in Caco-2 cells treated with TGF- or transfected with SMADs. Hence, TGF- activates SMADs that bind to the 485-bp intestinal enhancer element in the apob gene and increase its transcription and secretion in Caco-2 cells. This is the first example showing differential transcriptional regulation of the apob gene by cytokines and dissimilar regulation of one gene in two different cell lines by TGF-. In this regulation, the presence of cytokine-responsive motif in the tissue-specific enhancer element confers cell-specific response.

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