1387

CREBBP

CBP|KAT3A|RSTS;CREB binding protein;CREBBP;CREB binding protein

CREB-binding protein

16p13.3

protein-coding

CBP is a multifunctional transcriptional cofactor with tumor suppressor activity. The CH3 domain of CBP binds numerous transcription factors and several viral oncoproteins. We identified the Src substrate and RNA-binding protein Sam68 as novel CH3-binding protein. Sam68 binds the CH3 domain in part through a conserved FXD/EXXXL motif that is shared among several CH3-binding proteins, including the adenoviral oncoprotein E1A and the tumor suppressor p53. Sam68 and CBP interact in vivo and colocalize in nuclear sub-domains. Sam68 has potent transcriptional repression activity that is independent of its RNA binding activity, which suggests that RNA processing and regulation of gene expression by Sam68 are separable functions. Consistent with this, CBP did not stimulate the ability of Sam68 to promote Rev response element-containing mRNA export. Interestingly, Sam68 can regulate RNA processing in the absence of a Rev response element, suggesting that Sam68 functions through a novel RNA element. Together, these findings reveal a previously unidentified function for Sam68 as a transcriptional repressor and suggest that Sam68 might link cellular signaling pathways with components of the transcriptional machinery.

Substantial evidence has been accumulated suggesting that T cells in patients with epithelial ovarian carcinoma (EOC) exhibit an antigen-driven immune response directed against the tumor cells. In the context of human leukocyte antigen (HLA), this suggests its possible involvement in the disease. Therefore, we examined the distribution of the HLA-DRB1*, -DQA1*, and -DQB1* alleles in 47 patients with EOC and 67 healthy Caucasian women. The frequency of D(70) and E(71) polymorphic residues of the DRB1 alleles was significantly reduced in EOC patients versus controls (pD(70)E(71) = 0.009), suggesting a protective role against the disease. The DQalpha residues R(52) and Y(11)R(55) were increased in the patients (p = 0.008 and 0.012, respectively). Because residues 11 and 55 participate in the formation of pocket 1, they may be functionally important amino acid positions that influence disease susceptibility. The frequency of the DQalpha susceptibility epitope (R(52)Y(11)R(55)) among the DRbetaD(70)E(71)-positive EOC patients was increased when compared with DRbetaD(70)E(71)-positive controls (EOC, 100%; control, 52%; p = 0.028). Among individuals without the DQalpha susceptibility epitope, the distribution of DRbetaD(70)E(71)-positive cases was significantly different between EOC patients and controls (EOC, 0%; control, 60%; p = 0.039). Therefore, it appears that the presence of DQalpha susceptibility elements overrides the protective effect of the DRbetaD(70)E(71) epitope and suggests an interactive relationship between DRbeta and DQalpha epitopes that may be of importance for disease susceptibility. Because positions DRbeta 70,71 and DQalpha 52 have been implicated in immunologic diseases, it is likely that besides being critical for T-cell recognition, they may also play a role in T-cell development and acquisition of the T-cell repertoire.