Differential activities of E2F family members: Unique functions in regulating transcription

Pierce, Angela; Schneider‐Broussard, Robin; Philhower, Jennifer L.; Johnson, D. Gale

doi:10.1002/(sici)1098-2744(199807)22:3<190::aid-mc7>3.0.co;2-p

Cited by 40 publications

(27 citation statements)

References 43 publications

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“…To that end, the GAL4-E2F chimeric proteins showed that the E2F-1 transactivation domain is much more potent than the E2F-4 transactivation domain (data not shown). This is consistent with previous work (73). Many reports suggest that E2F transcriptional activating and repressing activities are mediated by different family members.…”

Section: Discussionsupporting

confidence: 94%

E2F Transcriptional Activation Requires TRRAP and GCN5 Cofactors

Lang

McMahon

Cole

et al. 2001

Journal of Biological Chemistry

115

101

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The E2F family of transcription factors regulates the temporal transcription of genes involved in cell cycle progression and DNA synthesis. E2F transactivation is antagonized by retinoblastoma protein (pRb), which recruits chromatin-remodeling proteins such as histone deacetylases and SWI⅐SNF complexes to the promoter to repress transcription. We hypothesized that E2F proteins must reverse the pRb-imposed chromatin structure to stimulate transcription. If this is true, E2F proteins should recruit proteins capable of histone acetylation. Here we map the E2F-4 transactivation domain and show that E2F-1 and E2F-4 transactivation domains bind the acetyltransferase GCN5 and cofactor TRRAP in vivo. TRRAP and GCN5 co-expression stimulated E2F-mediated transactivation, and c-Myc repressed E2F transactivation dependent on an intact TRRAP/GCN5 binding motif. The transactivation domain of E2F-4 recruited proteins with significant histone acetyltransferase activity in vivo, and this activity required catalytically active GCN5. E2F-4 proteins with subtle mutations in the transactivation domain exhibited a positive correlation among transcriptional activation and GCN5 and TRRAP binding capacity and associated acetyltransferase activity. We conclude that E2F stimulates transcription by recruiting acetyltransferase activity and the essential cofactors GCN5 and TRRAP. These results provide a mechanism for E2F transcription factors to overcome pRb-mediated dominant repression of transcription.The cell cycle is regulated in part by the temporal expression of specific genes. A transcription factor can control the timely induction of S phase-specific genes by either activating gene expression shortly before and during S phase or repressing expression during the remainder of the cell cycle. The E2F family of transcription factors is thought to contribute to cell cycle regulation through both mechanisms. E2F is likely to be a critical factor in cell growth regulation in vivo since most if not all human cancers contain a disruption in the E2F regulatory pathway (1).Consistent with this, enforced expression of E2F proteins drives quiescent cells into S phase and transforms cells in conjunction with activated Ras (2-6). Furthermore, E2F binding sites are found in the promoters of numerous genes whose expression is necessary for the initiation of S phase and DNA replication (7-9).DNA binding activity of the E2F transcription factor family is composed of two subunits, E2F and DP, which form heterodimeric complexes with a high affinity for the DNA sequence 5Ј-TTTCGCG-3Ј (7-9). Currently, the mammalian E2F family consists of six E2F and two DP genes. The DNA binding, heterodimerization, and marked box domains are highly conserved among all E2F family members. E2F-1, -2, and -3 have an extended N-terminal region containing a nuclear localization signal and binding sites for cyclin A, the transcription factor Sp1, and the E3 ubiquitin ligase complex SCF⅐SKP2 (10 -17). E2F-4, -5, and -6 lack these sequences. E2Fs 1-5 have an acidic transactivat...

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Section: Discussionsupporting

confidence: 94%

E2F Transcriptional Activation Requires TRRAP and GCN5 Cofactors

Lang

McMahon

Cole

et al. 2001

Journal of Biological Chemistry

115

101

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“…However, we do not believe this is the case since the levels of hyperproliferation and hyperplasia is similar or higher in the E2F4 and E2F3 transgenic models compared to K5 E2F1 transgenic mice. 32,33,38,39 As mentioned, both E2F1 and E2F3 have been shown to have tumor-suppressive activities. One example of E2F1's ability to inhibit tumorigenesis is the resistance of K5 E2F1 transgenic mice to two-stage skin carcinogenesis.…”

Section: Discussionmentioning

confidence: 94%

E2F3a Stimulates Proliferation, p53-Independent Apoptosis and Carcinogenesis in a Transgenic Mouse Model

2005

Self Cite

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=2307 KEY WORDSE2F3, cell cycle, transgenic mouse, apoptosis, skin carcinogenesis ABBREVIATIONS RbRetinoblastoma ABSTRACTMutation or inactivation of the retinoblastoma (Rb) tumor suppressor occurs in most human tumors and results in the deregulation of several members of the E2F family of transcription factors. Among the E2F family, E2F3 has been implicated as a key regulator of cell proliferation and E2F3 gene amplification and overexpression is detected in some human tumors. To study the role of E2F3 in tumor development, we established a transgenic mouse model expressing E2F3a in a number of epithelial tissues via a keratin 5 (K5) promoter. Transgenic expression of E2F3a leads to hyperproliferation, hyperplasia and increased levels of p53-independent apoptosis in transgenic epidermis. Consistent with data from human cancers, the E2F3a transgene is found to have a weak oncogenic activity on its own and to significantly enhance the response to a skin carcinogenesis protocol. The phenotype of K5 E2F3a transgenic mice is distinct from similar transgenic mice expressing E2F1 or E2F4. In particular, E2F3a has a unique apoptotic activity and lacks the tumor suppressive property of E2F1 in this model system.

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“…In addition, the miR-29 and E2F family members are known to be involved in ECM remodeling and cell proliferation, respectively (25,26). The E2F TF family contains nine members: E2F1, E2F2, and E2F3a are transcription activators, and the rest of the members are transcriptional suppressors (27). The balance of activation and suppression activities is critical for the precise control of cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Molecular evidence of stress-induced acute heart injury in a mouse model simulating posttraumatic stress disorder

Cho

Lee

Hammamieh

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Posttraumatic stress disorder (PTSD) is a common condition induced by life-threatening stress, such as that experienced by soldiers under battlefield conditions. Other than the commonly recognized behavioral and psychological dysfunction, epidemiological studies have also revealed that PTSD patients have a higher risk of other diseases, such as cardiovascular disorders. Using a PTSD mouse model, we investigated the longitudinal transcriptomic changes in heart tissues after the exposure to stress through intimidation. Our results revealed acute heart injury associated with the traumatic experience, reflecting the underlying biological injury processes of the immune response, extracellular matrix remodeling, epithelial-to-mesenchymal cell transitions, and cell proliferation. Whether this type of injury has any longterm effects on heart function is yet to be determined. The differing responses to stress leading to acute heart injury in different inbred strains of mice also suggest that this response has a genetic as well as an environmental component. Accordingly, the results from this study suggest a molecular basis for the observed higher risk of cardiovascular disorders in PTSD patients, which raises the likelihood of cardiac dysfunction induced by long-term stress exposures.systems biology | transcriptome | microRNA

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Differential activities of E2F family members: Unique functions in regulating transcription

Cited by 40 publications

References 43 publications

E2F Transcriptional Activation Requires TRRAP and GCN5 Cofactors

E2F Transcriptional Activation Requires TRRAP and GCN5 Cofactors

E2F3a Stimulates Proliferation, p53-Independent Apoptosis and Carcinogenesis in a Transgenic Mouse Model

Molecular evidence of stress-induced acute heart injury in a mouse model simulating posttraumatic stress disorder

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