Abstract
The CCAAT-binding transcription factor NF-Y plays a central role in regulating cellular proliferation by controlling the expression of genes required for cell-cycle progression such as cyclin A, cyclin B1, cyclin B2, cdc25A, cdc25C, and cdk1. Here we show that unrestricted NF-Y activity leads to apoptosis in an E2F1- and wild-type p53 (wtp53)-dependent manner. Unrestricted NF-Y activity induced an increase in E2F1 mRNA and protein levels. Furthermore, NF-Y directly bound the E2F1 promoter and this correlated with the appearance of open chromatin marks. The ability of NF-Y to induce apoptosis was impaired in cells lacking E2F1 and wtp53. Moreover, NF-Y overexpression elicited phosphorylation of wt p53Ser18 in an E2F1-dependent manner. Our findings establish that NF-Y acts upstream of E2F1 in p53-mediated apoptosis.
Highlights
NF-Y is a ubiquitous protein, composed of 3 subunits, NFYA, -YB, and -YC, whose genes are highly conserved from yeast to mammals
We found that NF-YA overexpression led to more than 80% reduction of colony formation
This reduction was NF-YA specific, as ectopic expression of NF-YB had no effect (Fig. 1A). This is in good agreement with the notion that the NF-YA is the regulatory subunit of the complex
Summary
NF-Y is a ubiquitous protein, composed of 3 subunits, NFYA, -YB, and -YC, whose genes are highly conserved from yeast to mammals. All 3 subunits are required for NF-Y binding to the consensus sequence, the CCAAT-box. A bioinformatic analysis of promoters of cell-cycle regulatory genes shows an abundance of CCAAT boxes in promoters regulated during the G2/M transition [2]. Expression of the protein is modulated during the cell cycle [3] and its abrogation plays an important role in downregulating several cell-cycle control genes in differentiated muscle cells [5,6,7, 10]. It has been shown that NF-Y regulates gene expression in embryonic stem cells, where it is required for their proliferation [11]. Previous studies aimed at understanding the biological role of NF-Y took advantage of a loss of Authors' Affiliations: 1Experimental Oncology Department, Istituto Regina Elena and 2Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’Immacolata, IRCCS, Rome, Italy
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