Interactions between p300 and Multiple NF-Y Trimers Govern Cyclin B2 Promoter Function

Salsi, Valentina; Caretti, Giuseppina; Wasner, Mark; Reinhard, Wibke; Haugwitz, Ulrike; Engeland, Kurt; Mantovani, Roberto

doi:10.1074/jbc.m210065200

Cited by 70 publications

(74 citation statements)

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“…Because NF-Y is important for promoter activation, it came as no surprise that interactions between this factor and p300 surfaced. Indeed, dynamic recruitment of p300 together with NF-Y, has been documented on cell cycle regulated promoters Salsi et al, 2003;Di Agostino et al, 2006;Gurtner et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…NF-Y interacts with hGCN5 (Currie, 1998), and NF-YB is acetylated in Xenopus by p300, but the consequences of this modification have not been addressed (Li et al, 1998). In vivo studies by chromatin immunoprecipitation on cell cycleregulated promoters highlighted the dynamic behavior of NF-Y and HATs binding during cell cycle progression Salsi et al, 2003;Di Agostino et al, 2006). Because of the role of ubiquitylation and acetylation in regulating the stability of several transcription factors, we investigated whether the NF-Y complex was subjected to these posttranslational modifications.…”

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Posttranslational Regulation of NF-YA Modulates NF-Y Transcriptional Activity

Manni¹,

Caretti

Artuso³

et al. 2008

MBoC

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Here we show that the levels of NF-YA protein are regulated posttranslationally by ubiquitylation and acetylation. A NF-YA protein carrying four mutated lysines in the C-terminal domain is more stable than the wild-type form, indicating that these lysines are ubiquitylated Two of the lysines are acetylated in vitro by p300, suggesting a competition between ubiquitylation and acetylation of overlapping residues. Interestingly, overexpression of a degradation-resistant NF-YA protein leads to sustained expression of mitotic cyclin complexes and increased cell proliferation, indicating that a tight regulation of NF-YA levels contributes to regulate NF-Y activity. INTRODUCTIONThe CCAAT-binding transcription factor NF-Y is a heteromeric protein composed of three subunits, NF-YA, -YB, and -YC, all necessary for CCAAT binding (Mantovani, 1999). The NF-Y complex supports the basal transcription of a class of regulatory genes responsible for cell cycle progression, among which are mitotic cyclin complexes (Zwicker et al., 1995a,b;Bolognese et al., 1999;Farina et al., 1999;Korner et al., 2001;Gurtner et al., 2003Gurtner et al., , 2008Di Agostino et al., 2006). Knock-out mice clearly demonstrates that NF-Y dependent transcription is essential during early mouse development (Bhattacharya et al., 2003). The NF-Y function in proliferation is also demonstrated by the inhibition of DNA binding by endogenous NF-Y, resulting in retardation of fibroblast growth, which is brought about by overexpression of a dominant negative mutant of the NF-YA subunit (Hu and Maity, 2000). The differential expression of NF-YA, altering NF-Y CCAAT-binding activity, has been observed in several cell lines and tissues both during cell cycle progression and under specific conditions. NF-YA expression is modulated during the cell cycle, being high in G1, further increasing in S, and then decreasing in the G2/M phase (Bolognese et al., 1999). Reduction of NF-YA expression has been reported in IMR-90 fibroblasts after serum deprivation (Chang et al., 1994) and in human monocytes (Marziali et al., 1997). The NF-YA protein is not expressed in terminally differentiated C2C12 muscle cells and adult skeletal muscle tissues (Farina et al., 1999;Gurtner et al., 2003Gurtner et al., , 2008. These observations show that levels of NF-YA dictate the function of the NF-Y complex. Interestingly, control of NF-YA accumulation is posttranscriptional, because NF-YA mRNA is relatively constant in growing and differentiated cells (Bolognese et al., 1999;Farina et al., 1999). Yet, the mechanisms regulating the stability of the NF-YA protein remain unknown.The covalent addition of ubiquitin, a 76-amino acid protein highly conserved among eukaryotes, is an increasingly common posttranslation modification that controls both the expression and the activity of numerous proteins in the eukaryotic cell (Hershko and Ciechanover, 1998;Ciechanover et al., 2000). The ubiquitin-proteasome pathway is composed of the ubiquitin-conjugating system and the 26S proteasome; the latter contain...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Posttranslational Regulation of NF-YA Modulates NF-Y Transcriptional Activity

Manni¹,

Caretti

Artuso³

et al. 2008

MBoC

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“…Further, transcription factors other than NFY and Sp1 could also be involved in the binding and recruitment of HAT to the FPGS promoter. For instance, interactions between NFY and HAT proteins such as the coactivator p300 [66][67][68][69][70][71] have been described previously. This dual mechanism of regulation involving both HATs and HDACs has recently been shown for the TbRII promoter in which transforming growth factor-b expression was found to be induced both by trichostatin-A, a HDACI, and by acetylation of Sp1 after recruitment of PCAF/ p300 to an Sp1/NFY complex.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy

et al. 2010

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Children with acute lymphoblastic leukemia (ALL) diagnosed with resistant phenotypes, and those who relapse, have a dismal prognosis for cure. The antifolate methotrexate (MTX), a universal component of ALL therapies, is metabolized by folylpoly-c-glutamate synthetase (FPGS) into long-chain polyglutamates (MTX-PG 3À7 ), resulting in enhanced cytotoxicity from prolonged inhibition of dihydrofolate reductase (DHFR) and thymidylate synthetase (TS). Using DNaseI assays, we identified a hypersensitive site upstream from exon-1, suggesting chromatin remodeling could alter FPGS expression. We demonstrated that histone deacetylase-1 (HDAC1) is recruited by NFY and Sp1 transcription factors to the FPGS promoter in ALL cell lines. We examined the effect of histone deacetylase inhibitors (HDACIs) sodium butyrate and suberoylanilide hydroxamic acid (SAHA) on the expression of FPGS and other folate-related genes. HDACIs increased FPGS mRNA expression by 2-to 5-fold, whereas DHFR and TS mRNA expression was decreased. Combination treatment with MTX plus SAHA significantly increased cytotoxicity and apoptosis in B-and T-ALL cell lines as compared with each drug alone (CIp0.8). SAHA increased the intracellular accumulation of long-chain MTX-PG 3À7 . Therefore, HDACI-induced FPGS expression increases the accumulation of MTX-PG 3À7 and cytotoxicity in ALL cell lines, which is potentiated by DHFR and TS downregulation. The synergism exhibited by the combination of MTX and SAHA warrants clinical testing in ALL patients.

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“…The existence of multiple NF-Y type CCAAT boxes in promoters is common in cell cycle-regulated genes (Colter et al, 2005;Li et al, 1998;Muller et al, 2007). The boxes appear to recruit histone acetylase complexes such as p300 Salsi et al, 2003) and other TFs (Roder et al, 1999;Imbriano et al, 2005). Defects or malfunctioning of these CCAAT boxes have been linked to several diseases, including some forms of cancer (Farina et al, 1999;Pabst et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Genome wide study of NF-Y type CCAAT boxes in unidirectional and bidirectional promoters in human and mouse

Häkkinen

Healy

Jacobs

et al. 2011

Journal of Theoretical Biology

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International audienceA subset of CCAAT boxes are known binding sites for the transcription factor NF-Y. We characterize their number, mismatches to the consensus sequence, and locations in bidirectional and unidirectional promoter sequences in human and mouse. We confront the findings with an analytical null model of DNA sequences and find that NF-Y type CCAAT boxes play key, but distinct roles in the two types of promoters. They are found above chance in both, but in unidirectional only when having few mismatches. In bidirectional, the relative positions of multiple boxes differ from what is expected by chance, suggesting the need for contiguity. In agreement, when there are four boxes (four-box configurations), these have much lower number of mismatches than expected in bidirectional promoters alone. Positioning of the first box differs in the two types of promoters and the null model, and mismatches and positioning are found to be correlated. Finally, four-box configurations are conserved between human and mouse, supporting the relevance of the findings. We conclude that bidirectional and unidirectional promoters, while sharing some similarities, appear to possess distinct regulatory mechanisms at the sequence level

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Interactions between p300 and Multiple NF-Y Trimers Govern Cyclin B2 Promoter Function

Cited by 70 publications

References 50 publications

Posttranslational Regulation of NF-YA Modulates NF-Y Transcriptional Activity

Posttranslational Regulation of NF-YA Modulates NF-Y Transcriptional Activity

Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy

Genome wide study of NF-Y type CCAAT boxes in unidirectional and bidirectional promoters in human and mouse

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