bIt is well recognized that PIAS1, a SUMO (small ubiquitin-like modifier) E3 ligase, modulates such cellular processes as cell proliferation, DNA damage responses, and inflammation responses. Recent studies have shown that PIAS1 also plays a part in cell differentiation. However, the role of PIAS1 in adipocyte differentiation remains unknown. CCAAT/enhancer-binding protein  (C/EBP), a major regulator of adipogenesis, is a target of SUMOylation, but the E3 ligase responsible for the SUMOylation of C/EBP has not been identified. The present study showed that PIAS1 functions as a SUMO E3 ligase of C/EBP to regulate adipogenesis. PIAS1 expression was significantly and transiently induced on day 4 of 3T3-L1 adipocyte differentiation, when C/EBP began to decline. PIAS1 was found to interact with C/EBP through the SAP (scaffold attachment factor A/B/acinus/ PIAS) domain and SUMOylate it, leading to increased ubiquitination and degradation of C/EBP. C/EBP became more stable when PIAS1 was silenced by RNA interference (RNAi). Moreover, adipogenesis was inhibited by overexpression of wild-type PIAS1 and promoted by knockdown of PIAS1. The mutational study indicated that the catalytic activity of SUMO E3 ligase was required for PIAS1 to restrain adipogenesis. Importantly, the inhibitory effect of PIAS1 overexpression on adipogenesis was rescued by overexpressed C/EBP. Thus, PIAS1 could play a dynamic role in adipogenesis by promoting the SUMOylation of C/EBP.
bAdipogenesis is a multistep process by which 3T3-L1 preadipocytes differentiate into mature adipocytes through mitotic clonal expansion (MCE) and terminal differentiation. The CCAAT/enhancer-binding protein  (C/EBP) is an important transcription factor that takes part in both of these processes. C/EBP not only transactivates C/EBP␣ and the peroxisome proliferatoractivated receptor ␥ (PPAR␥), which cause 3T3-L1 preadipocytes to enter terminal adipocyte differentiation, but also is required to activate cell cycle genes necessary for MCE. The identification of potential cofactors of C/EBP will help to explain how C/EBP undertakes these specialized roles during the different stages of adipogenesis. In this study, we found that activating transcription factor 5 (ATF5) can bind to the promoter of C/EBP␣ via its direct interaction with C/EBP (which is mediated via the p300-dependent acetylation of ATF5), leading to enhanced C/EBP transactivation of C/EBP␣. We also show that p300 is important for the interaction of ATF5 with C/EBP as well as for the binding activity of this complex on the C/EBP␣ promoter. Consistent with these findings, overexpression of ATF5 and an acetylated ATF5 mimic both promoted 3T3-L1 adipocyte differentiation, whereas short interfering RNA-mediated ATF5 downregulation inhibited this process. Furthermore, we show that the elevated expression of ATF5 is correlated with an obese phenotype in both mice and humans. In summary, we have identified ATF5 as a new cofactor of C/EBP and examined how C/EBP and ATF5 (acetylated by a p300-dependent mechanism) regulate the transcription of C/EBP␣.
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