Transcription factor YY1: structure, function, and therapeutic implications in cancer biology

Abstract

The ubiquitous transcription factor Yin Yang 1 (YY1) is known to have a fundamental role in normal biologic processes such as embryogenesis, differentiation, replication, and cellular proliferation. YY1 exerts its effects on genes involved in these processes via its ability to initiate, activate, or repress transcription depending upon the context in which it binds. Mechanisms of action include direct activation or repression, indirect activation or repression via cofactor recruitment, or activation or repression by disruption of binding sites or conformational DNA changes. YY1 activity is regulated by transcription factors and cytoplasmic proteins that have been shown to abrogate or completely inhibit YY1-mediated activation or repression; however, these mechanisms have not yet been fully elucidated. Since expression and function of YY1 are known to be intimately associated with progression through phases of the cell cycle, the physiologic significance of YY1 activity has recently been applied to models of tumor biology. The majority of the data are consistent with the hypothesis that YY1 overexpression and/or activation is associated with unchecked cellular proliferation, resistance to apoptotic stimuli, tumorigenesis and metastatic potential. Studies involving hematopoetic tumors, epithelial-based tumors, endocrine organ malignancies, hepatocellular carcinoma, and retinoblastoma support this hypothesis. Molecular mechanisms that have been investigated include YY1-mediated downregulation of p53 activity, interference with poly-ADP-ribose polymerase, alteration in c-myc and nuclear factor-kappa B (NF-kappaB) expression, regulation of death genes and gene products, and differential YY1 binding in the presence of inflammatory mediators. Further, recent findings implicate YY1 in the regulation of tumor cell resistance to chemotherapeutics and immune-mediated apoptotic stimuli. Taken together, these findings provide strong support of the hypothesis that YY1, in addition to its regulatory roles in normal biologic processes, may possess the potential to act as an initiator of tumorigenesis and may thus serve as both a diagnostic and prognostic tumor marker; furthermore, it may provide an effective target for antitumor chemotherapy and/or immunotherapy.

Regulatory polymorphisms in the bovine Ankyrin 1 gene promoter are associated with tenderness and intramuscular fat content

“…Adamowicz and co-workers [47] also reported that a mutation in the Sp1 binding site of the bovine leptin gene affects its expression level. The presence of a G allele of this SNP (rSNP4) created a binding site for the zinc finger nuclear protein, YY1 (Yin Yang 1), also known as NF-E1, UCRBP or CF1, which is known to have fundamental roles in repressing and activating a diverse group of promoters; it not only initiates transcription but also activates or represses it [48,49]. YY1 is also shown to repress muscle specific expression of sarcomeric alpha-actin and c-myc genes [49].…”

Cooperation between Myc and YY1 provides novel silencing transcriptional targets of α3β1-integrin in tumour cells

“…This element is sufficient to regulate positively the transcription in normal cells and negatively in osteosarcoma cells. There are several possible mechanisms of the negative action of YY1 (Gordon et al, 2006). It can block the transcription through the interaction with transcription factors masking their activation domain or recruitment of corepressor molecules or, finally, by modifying histones to induce a close chromatin state (Hynes, 2002).…”

“…Electrophoretic mobility shift assay Nuclear extracts were prepared as described Gordon et al, 2006). Protein concentration was determined by the Bradford method .…”

“…The cell sorter was performed using 500 Â 10 3 stained with b1-integrin phycoerythrin antibody (CD20) from Santa Cruz, and analysed in a FACScan flow cytometer (Becton Dickinson, Flanklin Lakes, NJ, USA), as described Gordon et al, 2006). Non-immune mouse IgG was used as the negative control.…”

Increased expression of nucleophosmin/B23 in hepatocellular carcinoma and correlation with clinicopathological parameters

“…Although the process of hepatocarcinogenesis has not yet been fully elucidated, it is considered a multifactorial and multistep process that involves the activation of oncogenes or the inactivation of tumour suppressor genes during the different stages of HCC progression. Several studies have recently shown that activation of oncogenes was involved in hepatocarcinogenesis, genes such as cyclin D1 (Deane et al, 2001), the transcription factor Yin Yang 1 (YY1) (Gordon et al, 2006), and the hedgehog pathway (Sicklick et al, 2006). Overexpression of cyclin D1 has been shown to be sufficient for the initiation of hepatocellular carcinogenesis in a transgenic mouse model (Deane et al, 2001).…”