The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis. Nascimento, EM; Cox, CL; MacArthur, S; Hussain, S; Trotter, M; Blanco, S; Suraj, M; Nichols, J; Kübler, B; Benitah, SA; Hendrich, B; Odom, DT; Frye, M Nature cell biology
13
1395-405
2011
Show Abstract
How the proto-oncogene c-Myc balances the processes of stem-cell self-renewal, proliferation and differentiation in adult tissues is largely unknown. We explored c-Myc's transcriptional roles at the epidermal differentiation complex, a locus essential for skin maturation. Binding of c-Myc can simultaneously recruit (Klf4, Ovol-1) and displace (Cebpa, Mxi1 and Sin3a) specific sets of differentiation-specific transcriptional regulators to epidermal differentiation complex genes. We found that Sin3a causes deacetylation of c-Myc protein to directly repress c-Myc activity. In the absence of Sin3a, genomic recruitment of c-Myc to the epidermal differentiation complex is enhanced, and re-activation of c-Myc-target genes drives aberrant epidermal proliferation and differentiation. Simultaneous deletion of c-Myc and Sin3a reverts the skin phenotype to normal. Our results identify how the balance of two transcriptional key regulators can maintain tissue homeostasis through a negative feedback loop. | | 22101514
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Transcription factor AP-2 interacts with the SUMO-conjugating enzyme UBC9 and is sumolated in vivo. Eloranta, Jyrki J and Hurst, Helen C J. Biol. Chem., 277: 30798-804 (2002)
2002
Show Abstract
The members of the AP-2 family of transcription factors are developmentally regulated and have distinct yet overlapping functions in the regulation of many genes governing growth and differentiation. All AP-2 factors appear to be capable of binding very similar DNA recognition sites, and the determinants of functional specificity remain to be elucidated. AP-2 transcription factors have been shown to act both as transcriptional activators and repressors in a promoter-specific manner. Although several mediators of their activation function have been suggested, few mechanisms for the repression or down-regulation of transactivation have been described. In a two-hybrid screen for proteins interacting with AP-2 factors, we have identified the UBC9 gene that encodes the E2 (ubiquitin carrier protein)-conjugating enzyme for the small ubiquitin-like modifier, SUMO. The interaction domain resides in the C-terminal half of AP-2, which contains the conserved DNA binding and dimerization domains. We have detected sumolated forms of endogenous AP-2 in mammalian cells and have further mapped the in vivo sumolation site to conserved lysine 10. Transient transfection studies indicate that sumolation of AP-2 decreases its transcription activation potential, and we discuss the possible mechanisms for the observed suppression of AP-2 transactivation. | Immunoblotting (Western) | 12072434
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