Post-transcriptional up-regulation of Tsc-22 by Ybx1, a target of miR-216a, mediates TGF-{beta}-induced collagen expression in kidney cells.

Abstract

Increased accumulation of extracellular matrix proteins and hypertrophy induced by transforming growth factor-β1 (TGF-β) in renal mesangial cells (MC) are hallmark features of diabetic nephropathy. Although the post-transcriptional regulation of key genes has been implicated in these events, details are not fully understood. Here we show that TGF-β increased microRNA-216a (miR-216a) levels in mouse MC, with parallel down-regulation of Ybx1, a miR-216a target and RNA-binding protein. TGF-β also enhanced protein levels of Tsc-22 (TGF-β-stimulated clone 22) and collagen type I α-2 (Col1a2) expression in MC through far upstream enhancer E-boxes by interaction of Tsc-22 with an E-box regulator, Tfe3. Ybx1 colocalized with processing bodies in MC and formed a ribonucleoprotein complex with Tsc-22 mRNA, and this complex formation was reduced by TGF-β, miR-216a mimics, or Ybx1 shRNA to increase Tsc-22 protein levels but enhanced by miR-216a inhibitor oligonucleotides. Chromatin immunoprecipitation (ChIP) assays revealed that TGF-β could increase the occupancies of Tsc-22 and Tfe3 on enhancer E-boxes of Col1a2. Co-immunoprecipitation assays revealed that TGF-β promoted the interaction of Tsc-22 with Tfe3. These results demonstrate that post-transcriptional regulation of Tsc-22 mediated through Ybx1, a miR-216a target, plays a key role in TGF-β-induced Col1a2 in MC related to the pathogenesis of diabetic nephropathy.

• Authors: Mitsuo Kato, Lin Wang, Sumanth Putta, Mei Wang, Hang Yuan, Guangdong Sun, Linda Lanting, Ivan Todorov, John J Rossi, Rama Natarajan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 44 Pg. 34004-15 (Oct 29 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20713358 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• MIRN216 microRNA, mouse
• MicroRNAs
• RNA, Messenger
• Repressor Proteins
• Tgfb1i4 protein, mouse
• Transcription Factors
• Transforming Growth Factor beta
• YB-1 protein, mouse

Topics

• Animals
• Diabetic Nephropathies (metabolism)
• Enhancer Elements, Genetic
• Gene Expression Regulation
• Humans
• Kidney (metabolism)
• Mice
• Mice, Inbred C57BL
• MicroRNAs (metabolism)
• RNA Processing, Post-Transcriptional
• RNA, Messenger (metabolism)
• Repressor Proteins (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription Factors (metabolism)
• Transforming Growth Factor beta (metabolism)