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Cell cycle regulation of cdc25C transcription is mediated by the periodic repression of the glutamine-rich activators NF-Y and Sp1.

ABSTRACT: The late S/G2-specific transcription of the human cdc25C gene is dependent on an initiator-proximal repressor element (CDE) and an upstream activating sequence (UAS) of undefined nature. We now show that these upstream sequences harbour multiple in vivo protein binding sites that interact with transcriptional activators and form separable, context-independent functional modules. Major components of the UAS are a bona fide Sp1 site and three direct sequence repeats (Yc-boxes). The Yc-boxes interact with the CCAAT-box binding protein NF-Y and are critically dependent on synergistic interactions for efficient transcription activation. The NF-Y complexes, as well as Sp1, are constitutive activators, whose activation function is periodically repressed through the CDE. These observations indicate that the cell cycle regulation of cdc25C transcription is mainly due to the CDE-mediated repression of glutamine-rich activators.

SUBMITTER: Zwicker J

PROVIDER: S-EPMC307297 | biostudies-other | 1995 Oct

REPOSITORIES: biostudies-other

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Cell cycle regulation of cdc25C transcription is mediated by the periodic repression of the glutamine-rich activators NF-Y and Sp1.

Zwicker J J Gross C C Lucibello F C FC Truss M M Ehlert F F Engeland K K Müller R R

Nucleic acids research 19951001 19

The late S/G2-specific transcription of the human cdc25C gene is dependent on an initiator-proximal repressor element (CDE) and an upstream activating sequence (UAS) of undefined nature. We now show that these upstream sequences harbour multiple in vivo protein binding sites that interact with transcriptional activators and form separable, context-independent functional modules. Major components of the UAS are a bona fide Sp1 site and three direct sequence repeats (Yc-boxes). The Yc-boxes intera ...[more]

PMID: 7479023

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Project description:BACKGROUND:The ubiquitous transcription factor Sp1 regulates the expression of a vast number of genes involved in many cellular functions ranging from differentiation to proliferation and apoptosis. Sp1 expression levels show a dramatic increase during transformation and this could play a critical role for tumour development or maintenance. Although Sp1 deregulation might be beneficial for tumour cells, its overexpression induces apoptosis of untransformed cells. Here we further characterised the functional and transcriptional responses of untransformed cells following Sp1 overexpression. METHODOLOGY AND PRINCIPAL FINDINGS:We made use of wild-type and DNA-binding-deficient Sp1 to demonstrate that the induction of apoptosis by Sp1 is dependent on its capacity to bind DNA. Genome-wide expression profiling identified genes involved in cancer, cell death and cell cycle as being enriched among differentially expressed genes following Sp1 overexpression. In silico search to determine the presence of Sp1 binding sites in the promoter region of modulated genes was conducted. Genes that contained Sp1 binding sites in their promoters were enriched among down-regulated genes. The endogenous sp1 gene is one of the most down-regulated suggesting a negative feedback loop induced by overexpressed Sp1. In contrast, genes containing Sp1 binding sites in their promoters were not enriched among up-regulated genes. These results suggest that the transcriptional response involves both direct Sp1-driven transcription and indirect mechanisms. Finally, we show that Sp1 overexpression led to a modified expression of G1/S transition regulatory genes such as the down-regulation of cyclin D2 and the up-regulation of cyclin G2 and cdkn2c/p18 expression. The biological significance of these modifications was confirmed by showing that the cells accumulated in the G1 phase of the cell cycle before the onset of apoptosis. CONCLUSION:This study shows that the binding to DNA of overexpressed Sp1 induces an inhibition of cell cycle progression that precedes apoptosis and a transcriptional response targeting genes containing Sp1 binding sites in their promoter or not suggesting both direct Sp1-driven transcription and indirect mechanisms.

Dataset Information

Cell cycle regulation of cdc25C transcription is mediated by the periodic repression of the glutamine-rich activators NF-Y and Sp1.

Publications

Cell cycle regulation of cdc25C transcription is mediated by the periodic repression of the glutamine-rich activators NF-Y and Sp1.

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