Disease relevance of NFYA

• The NF-Y complex derived from class II+ mature B-cells bound with high affinity to anion exchangers, and eluted as an intact trimeric complex, whereas, NF-Y derived from class II- plasma B-cells, and from bare lymphocyte syndrome group II cell lines, RJ2.2.5 and RM3, dissociated into discrete NF-YA and NF-YB:C subunit fractions [1].
• Chromosomal translocations involving the human CBFB gene, which codes for the non-DNA binding subunit of CBF (CBF beta), are associated with a large percentage of human leukemias [2].
• Core binding factor beta (CBFB) haploinsufficiency due to an interstitial deletion at 16q21q22 resulting in delayed cranial ossification, cleft palate, congenital heart anomalies, and feeding difficulties but favorable outcome [3].
• In contrast, the CBFbeta-smooth muscle myosin heavy chain (SMMHC) fusion protein generated by the inv(16) associated with acute myeloid leukemias (M4Eo) cannot rescue definitive hematopoiesis by Cbfb-deficient ES cells [4].
• The haplotype including wild-type alleles of these SNPs (C/G/G/T/C/G, HAP2) is identified as a risk factor for morbid obesity (P = 0.003) [5].

High impact information on NFYA

• This higher affinity provides an explanation for the dominant negative phenotype associated with a knock-in of the CBFB-MYH11 gene and also helps to provide a rationale for the leukemia-associated dysregulation of hematopoietic development that this protein causes [2].
• We examined the collective role of core-binding factors in hematopoiesis with a hypomorphic Cbfb allelic series [6].
• In particular, NFYA and NFYC bound RFXANK/B in vitro [7].
• Role of Cbfb in hematopoiesis and perturbations resulting from expression of the leukemogenic fusion gene Cbfb-MYH11 [8].
• This population of stem cells and progenitors was not present in mouse embryos heterozygous for the Cbfb-MYH11 knock-in gene [8].

Biological context of NFYA

• Thus, the cellular distributions of these alternatively spliced NF-YA isoforms could impart an important cell-specific component to CBS transcriptional regulation, by virtue of their abilities to directly synergize with Sp1/Sp3 and interfere with transactivation of the CBS-1b promoter by wild-type NF-Y [9].
• Zinc-fingers and homeoboxes (ZHX) 1 is a transcription factor that interacts with the activation domain of the A subunit of nuclear factor-Y (NF-YA) [10].
• Lastly, the dimerization domain, the interaction domain with NF-YA, and the repressor domain are mapped to a region including the HD1 region, and two nuclear localization signals are mapped to the N-terminal through Znf1 and the HD2 region, respectively [11].
• We used the yeast two-hybrid system to show that the serum response factor (SRF) and zinc-fingers and homeobox 1 (ZHXI) proteins interact with the A subunit of nuclear factor-Y (NF-YA) [12].
• Gel mobility shift and DNA footprinting assays indicated that NFYA and LSF bound the CAAT and LSF motifs, respectively, and GAL4-NFYA/GAL4-LSF chimeras were also activated by E2, 8-bromo-cAMP, and protein kinase A (PKA) expression plasmid [13].

Anatomical context of NFYA

• Moreover, gel shift and supershift analyses with the nuclear extracts prepared from HCT116 cells identified NF-YA as the transcription factor interacting with the inverted CCAAT box [14].
• An NF-YA trans-dominant mutant decreased TRBP1 promoter expression fourfold in Jurkat cells, thus demonstrating the functional importance of NF-Y factors in lymphocytes [15].
• However, HLA-DR expression could be restored by transfection with NF-YA driven by a CMV promoter, although HLA-DR failed to localize in either the late endosomes, lysosomes, or acidic compartments [16].
• In fact, sucrase-isomaltase, apolipoprotein A1, and H-ferritin were constitutively expressed in NF-YA-transfected cells and their levels did not increase during prolonged culture, while these markers were not expressed in mock-transfected CaCo-2 cells or transfected with an inactive NF-YA expression vector until the onset of differentiation [17].
• Possible role of subunit A of nuclear factor Y (NF-YA) in normal human diploid fibroblasts during senescence [18].

Associations of NFYA with chemical compounds

• Transcription factors NF-YA regulate the induction of human OGG1 following DNA-alkylating agent methylmethane sulfonate (MMS) treatment [14].
• Synergistic regulation of human cystathionine-beta-synthase-1b promoter by transcription factors NF-YA isoforms and Sp1 [9].
• Seven unique NF-YA isoforms were detected in HT1080 by reverse transcriptase-PCR (RT-PCR) and DNA sequencing, characterized by deletions in the glutamine-rich and/or serine/threonine-rich domains [9].
• Our results suggest that suppression of NF-YA levels is one of the mechanisms whereby dexamethasone reduces hormone-induced TbetaRI and TbetaRII mRNA levels in hamster preantral follicles [19].

Physical interactions of NFYA

• Moreover, ZHX2 interacts with the activation domain of NF-YA [10].

Regulatory relationships of NFYA

• Transcription factors Oct-1 and NF-YA regulate the p53-independent induction of the GADD45 following DNA damage [20].

Other interactions of NFYA

• Overall, these results demonstrate that MMS can up-regulate hOGG1 expression through the induction of the transcription factor, NF-YA, and increased transcription level of the hOGG1 gene correlates with an increase in enzyme activity providing functional protection from MMS [14].
• A dominant negative mutant of NF-YA abolished the effect of p53 on Chk2 promoter activity [21].
• Amino acids located between 272 and 564, a region that contains two homeodomains, are required for the interaction of ZHX1 with NF-YA [12].
• Moreover, NF-YA and P/CAF were shown to interact in vitro [22].
• Sedimentation velocity centrifugation experiments confirm that two pools of NF-YB, and most likely NF-YC, exist: one associated with NF-YA and binding to the CCAAT box; another involved in high molecular weight complexes [23].

Analytical, diagnostic and therapeutic context of NFYA

• Lastly, using an immunoprecipitation assay, we showed that ZHX2 intrinsically interacts with NF-YA in HEK-293 cells and that ZHX2 represses the promoter activity of the cdc25C gene stimulated by NF-Y in Drosophila Schneider line 2 cells [10].
• Moreover, the Electrophoretic Mobility Shift Assay (EMSA) has demonstrated the direct bindings of Oct-1 and NF-YA proteins to their consensus sequences in the GADD45 promoter [20].

References