YB-1 Regulation of the Human and Rat Gelatinase A Genes via Similar Enhancer Elements

Abstract

Abstract. Experimental and clinical studies strongly suggest that gelatinase A plays a central role in the evolution of glomerular injury and sclerosis. The sequences of the 5′ flanking regions of the human and rat gelatinase A genes do not share similarities with other members of the matrix metallo-proteinase gene family and are regulated in a distinctive manner. The human and rat gelatinase A genes include regions of significant homology (r2 human; RE-1 rat), which have been shown to act as potent cis-activators of transcription. The rat RE-1 sequence interacts specifically with the developmentally regulated transcription factors AP2 and YB-1, resulting in a synergistic activation of gelatinase A transcription. Although the human r2 sequence specifically interacts with AP2 (Mol Cell Biol 10: 6524-6532, 1990), there is no clear evidence for the presence of a canonical YB-1 binding site (Y-box) within this sequence. This study demonstrates, despite the absence of a canonical Y-box sequence in the r2 element, that YB-1 and AP2 specifically interact with r2, yielding synergistic transactivation of the human gelatinase A gene. It is concluded that the r2 element is the conserved functional analog of the RE-1 element, and that interactions of AP2 and YB-1 govern human gelatinase A gene expression.

YB-1 promotes strand separation in vitro of duplex DNA containing either mispaired bases or cisplatin modifications, exhibits endonucleolytic activities and binds several DNA repair proteins

“…It was originally identi®ed by its ability to bind to the inverted CCAAT box (Y-box) in the promoter region of MHC class II genes (1). Subsequently, YB-1 has been shown to regulate the expression of a number of genes including proliferating cell nuclear antigen (PCNA) (2), thymidine kinase (3), DNA polymerase a (4), myosin lightchain 2v gene (5), Fas antigen (6), collagen a1(I) gene (7), protein tyrosine phosphatase 1B (PTP1B) gene (8), gelatinase A (9) and the multidrug resistance (MDR1) gene (10,11). In addition to the regulation of transcription, YB-1 is a multifunctional protein that also affects the splicing and the translation of speci®c mRNAs.…”

Comparative Analysis of Acute Kidney Injury Models and Related Fibrogenic Responses: Convergence on Methylation Patterns Regulated by Cold Shock Protein

“…In healthy tissue, the extracellular matrix undergoes constant remodeling, with an equilibrium between synthesis and degradation [ 49 ]. MMP2 drew our attention as it is implicated in the initiation and progression of kidney fibrosis and its gene transcription is regulated by YB-1 [ 48 , 50 ]. The UUO animals exhibited enhanced MMP2 gene expression and enzymatic activity in wild-type strains ( Figure 3 e,f).…”

“…This finding suggests a YB-1-dependent recruitment of DNMT1 to Klotho, potentially explaining how YB-1 influences Klotho methylation. We further investigated YB-1’s role in Klotho methylation by analyzing the sequence of the Klotho promoter region for YB-1 binding sites, using the Y-box (inverted CCAAT) sequence as a template [ 29 , 38 , 48 , 50 , 54 ]. YB-1 is known to bind to stem-loop structures that can form due to complementary base pairing.…”

An old friend with a new face: YB-1 and its role in healthy pregnancy and pregnancy-associated complications

“…Thereby, they became an interesting aspect of tumor biology and indeed MMPs are involved in all stages of carcinogenesis from proliferation to invasion and metastasis ( Kessenbrock et al, 2010 ). Interestingly, YB-1 regulates several matrix metalloproteinases including MMP-1 ( Lim et al, 2019 ), MMP-2 ( Mertens et al, 1999 ; Matsumoto et al, 2005 ), MMP-9 ( Stojanovska et al, 2021 ), MMP-11 ( Li et al, 2017 ), MMP-12 ( Samuel et al, 2005 ), MMP-13 ( Samuel et al, 2007 ), MMP-14 ( Lovett et al, 2010 ) and MMP-15 ( Shinkai et al, 2016 ). It does not only act as transcription and translation factor, but also promote the cellular turnover and recycling rates of MMPs and thereby modulate the invasive and metastatic potential of cancer cells ( Lovett et al, 2010 ; Lim et al, 2019 ).…”