1387

CREBBP

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

CREB-binding protein

16p13.3

protein-coding

Count: 1; Generif

We previously showed two members of the ING family, ING1 and ING3 as a tumor suppressor gene in head and neck cancer. Progress in human genome sequencing provided additional information of the new members of the ING family genes. ING4 is localized to chromosome 12p13.31 region and harbors the PHD domain highly homologous among ING family proteins. We analyzed loss of heterozygosity at 12p12-13 region in 50 head and neck squamous cell carcinomas by using six highly polymorphic microsatellite markers and found allelic loss in 66% (33/50) of the informative cases. To clarify the role of ING4 in head and neck carcinogenesis, we first checked mutation status in tumor samples. As mutation of the ING4 gene was not found in head and neck cancers, we examined the mRNA expression level. Quantitative real-time RT-PCR analysis demonstrated decreased expression of ING4 mRNA in 76% of primary tumors as compared with that of matched normal samples. Since p53 dependent pathways of other ING family members have been shown, we examined p53 mutation status and compared with ING4 mRNA expression in tumor samples. However, no such direct relationship has been detected. In conclusion, frequent deletion and decreased mRNA expression of ING4 suggested it as a class two tumor suppressor gene and may play an important role in head and neck cancer.

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.