Abstract
Williams-Beuren syndrome-associated transcription factor TFII-I plays a critical regulatory role in bone and neural tissue development and in immunity, in part by regulating cell proliferation in response to mitogens. Mdm2, a cellular oncogene responsible for the loss of p53 tumor suppressor activity in a significant proportion of human cancers, was identified in this study as a new binding partner for TFII-I and a negative regulator of TFII-I-mediated transcription. These findings suggest a new p53-independent mechanism by which increased Mdm2 levels found in human tumors could influence cancer cells. In addition to that, we present data indicating that TFII-I is an important cellular regulator of transcription from the immediate-early promoter of human cytomegalovirus, a promoter sequence frequently used in mammalian expression vectors, including vectors for gene therapy. Our observation that Mdm2 over-expression can decrease the ability of TFII-I to activate the CMV promoter might have implications for the efficiency of experimental gene therapy based on CMV promoter–derived vectors in cancers with Mdm2 gene amplification.
Highlights
A tight control of gene expression is critically important for proper regulation of cell growth, proliferation, survival and differentiation during development and for the maintenance of tissue homeostasis in a multicellular organism
As we had found that the endogenous levels of Mouse double minute 2 (Mdm2) were relatively low in HEK293T cells, just at the detection limit of the anti-Mdm2 antibody used in our experiments, we transiently transfected the cells with a plasmid coding for human Mdm2
Over-expressed Mdm2 accumulated in distinct nuclear domains and endogenous TFII-I followed the pattern of Mdm2 localization in Mdm2-overexpressing cells (Fig 1B)
Summary
A tight control of gene expression is critically important for proper regulation of cell growth, proliferation, survival and differentiation during development and for the maintenance of tissue homeostasis in a multicellular organism. This is achieved by a large number of transcription factors involved in the spatial and temporal control of gene activity in response to intraand extracellular signals. Williams-Beuren syndrome, a complex multisystemic genetic disorder characterized by a unique cognitive profile and craniofacial defects, results from a small deletion at the chromosomal location 7q11.23 that encompasses, among other genes, GTF2I, GTF2IRD1 and GTF2IRD2, encoding three members of TFII-I family of transcription factors [1]. The homozygous loss of either Gtf2ird or Gtf2i gene function results in multiple phenotypic manifestations, including embryonic lethality, brain hemorrhage, craniofacial malformations and PLOS ONE | DOI:10.1371/journal.pone.0144753 December 11, 2015
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