Transcription Control by E1A and MAP Kinase Pathway via Sur2 Mediator Subunit

Stevens, Jennitte; Cantin, Greg T.; Wang, Gang; Shevchenko, Andrej; Berk, Arnold

doi:10.1126/science.1068943

Cited by 220 publications

(253 citation statements)

References 18 publications

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“…The transcriptional activity of Elk-1 is also tightly regulated by protein-protein interactions. The interaction of Elk-1 with the coactivators CBP and/or Sur2 positively impacts Elk-1-mediated transcription events (Janknecht and Nordheim, 1996;Boyer et al, 1999;Nissen et al, 2001;Stevens et al, 2002). On the other hand, the association of Elk-1 with ID-1 and the histone deacetylase mSin3A negatively regulates Elk-1 transcriptional activity Roberts et al, 2001;Yang et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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Akt negatively regulates translation of the ternary complex factor Elk-1

Figueroa

Vojtek

2003

Oncogene

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Cross-talk between signaling pathways plays an important role in regulation of cell growth, differentiation, survival, and death. Here, we show that Akt regulates the Elk-1 transcription factor, independent of its negative regulation of Raf kinases. Using a constitutively active Mek1 to bypass the regulation of Raf by Akt, we find that the Elk-1 and Sap1a proteins are dramatically decreased in the presence of activated Akt. Akt catalytic activity is required. Also, Mek-dependent activation of a TCF (Elk-1/Sap-1a)-dependent c-fos reporter is decreased by activated Akt. Neither the level of Elk-1 mRNA nor the stability of the Elk-1 protein is altered by activated Akt. Instead, the rate of incorporation of labeled methionine into Elk-1 protein is decreased in the presence of Akt. In addition, the level of the Elk-1 protein but not GFP is significantly decreased in the presence of activated Akt, when GFP is expressed from an IRES element in a bicistronic message with Elk-1. We conclude that Akt negatively regulates translation of the Elk-1 mRNA. A coding region determinant that maps within the first 279 nts of the Elk-1 message is necessary and sufficient for Akt-mediated regulation of Elk-1.

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Section: Discussionmentioning

confidence: 99%

“…Erk phosphorylates and activates Elk-1 and Sap1a (Sharrocks et al, 2000). Phosphorylation of Elk-1 by Erk is important for its binding and/or functional cooperation with coactivators such as Sur2 and CBP (Janknecht and Nordheim, 1996;Stevens et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Akt negatively regulates translation of the ternary complex factor Elk-1

Figueroa

Vojtek

2003

Oncogene

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“…Identification of the CR3-interacting subunit in the Mediator allowed its function to be tested by isolating cells with a knockout of the Med23 gene (Stevens et al, 2002). CR3 AD function was eliminated in Med23À/À cells.…”

Section: E1a Conserved Region 3 Activation Of Early Viral Gene Expresmentioning

confidence: 99%

Recent lessons in gene expression, cell cycle control, and cell biology from adenovirus

2005

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Adenovirus continues to be an important model system for investigating basic aspects of cell biology. Interactions of several cellular proteins with E1A conserved regions (CR) 1 and 2, and inhibition of apoptosis by E1B proteins are required for oncogenic transformation. CR2 binds RB family members, de-repressing E2F transcription factors, thus activating genes required for cell cycling. E1B-19K is a BCL2 homolog that binds and inactivates proapoptotic BAK and BAX. E1B-55K binds p53, inhibiting its transcriptional activation function. In productively infected cells, E1B-55K and E4orf6 assemble a ubiquitin ligase with cellular proteins Elongins B and C, Cullin 5 and RBX1 that polyubiquitinates p53 and one or more subunits of the MRN complex involved in DNA doublestrand break repair, directing them to proteosomal degradation. E1A CR3 activates viral transcription by interacting with the MED23 Mediator subunit, stimulating preinitiation complex assembly on early viral promoters and probably also the rate at which they initiate transcription. The viral E1B-55K/E4orf6 ubiquitin ligase is also required for efficient viral late protein synthesis in many cell types, but the mechanism is not understood. E1A CR1 binds several chromatin-modifying complexes, but how this contributes to stimulation of cellular DNA synthesis and transformation is not clear. E1A CR4 binds the CtBP corepressor, but the mechanism by which this modulates the frequency of transformation remains to be determined. Clearly, adenovirus has much left to teach us about fundamental cellular processes.

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“…Although the mediator complex seems to be universally required for the transcription of all genes, specific subunits are dedicated to the regulation of distinct expression programmes by interactions with relevant genespecific transcriptional activators 22 . Recently, the mediator subunit Med23 (also known as Sur2) has attracted attention because it regulates the mitogen-activated protein kinase signalling pathway 24,25 . Med23 mediates the immediate early gene (IEG) response to serum mitogens, which is required for mediator recruitment to a small subset of genes that are predominantly controlled by the mitogen-activated protein kinase signalling pathway 24,25 .…”

mentioning

confidence: 99%

“…Recently, the mediator subunit Med23 (also known as Sur2) has attracted attention because it regulates the mitogen-activated protein kinase signalling pathway 24,25 . Med23 mediates the immediate early gene (IEG) response to serum mitogens, which is required for mediator recruitment to a small subset of genes that are predominantly controlled by the mitogen-activated protein kinase signalling pathway 24,25 . Moreover, Med23 has important roles in diverse biological processes including adipogenesis, brain development, cell differentiation and carcinogenesis [26][27][28][29] .…”

mentioning

confidence: 99%