Several peptide fragments are produced by proteolytic cleavage of the opioid peptide precursor proenkephalin A, and among these are a number of enkephalin fragments, in particular bovine adrenal medulla peptide 22 (BAM22). These peptide products have been implicated in diverse biological functions, including analgesia. We have cloned a newly identified family of 'orphan' G protein--coupled receptors (GPCRs) and demonstrate that BAM22 and a number of its fragments bind to and activate these receptors with nanomolar affinities. This family of GPCRs is uniquely localized in the human and rat small sensory neuron, and we called this family the sensory neuron--specific G protein--coupled receptors (SNSRs). Receptors of the SNSR family are distinct from the traditional opioid receptors in their insensitivity to the classical opioid antagonist naloxone and poor activation by opioid ligands. The unique localization of SNSRs and their activation by proenkephalin A peptide fragments indicate a possible function for SNSRs in sensory neuron regulation and in the modulation of nociception.
MicroRNAs (miRNAs) are a class of noncoding small RNAs that regulate gene expression by base pairing with target mRNAs at the 3′-terminal untranslated regions (3′-UTRs), leading to mRNA cleavage or translational repression. Single-nucleotide polymorphisms (SNPs) located at miRNA-binding sites (miRNA-binding SNPs) are likely to affect the expression of the miRNA target and may contribute to the susceptibility of humans to common diseases. We herein performed a genome-wide analysis of SNPs located in the miRNA-binding sites of the 3′-UTR of various human genes. We found that miRNA-binding SNPs are negatively selected in respect to SNP distribution between the miRNA-binding ‘seed’ sequence and the entire 3′-UTR sequence. Furthermore, we comprehensively defined the expression of each miRNA-binding SNP in cancers versus normal tissues through mining EST databases. Interestingly, we found that some miRNA-binding SNPs exhibit significant different allele frequencies between the human cancer EST libraries and the dbSNP database. More importantly, using human cancer specimens against the dbSNP database for case-control association studies, we found that twelve miRNA-binding SNPs indeed display an aberrant allele frequency in human cancers. Hence, SNPs located in miRNA-binding sites affect miRNA target expression and function, and are potentially associated with cancers.
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level to lead to mRNA degradation or repressed protein production. The expression of miRNA is deregulated in many types of cancers. To determine whether genetic alterations in miRNA genes are associated with cancers, we have systematically screened sequence variations in several hundred human miRNAs from >100 human tumor tissues and 20 cancer cell lines. We identified 8 new single-nucleotide polymorphisms (SNPs) and 14 novel mutations (or very rare SNPs) that specifically present in human cancers. These mutations/SNPs are distributed in the regions of pri-, pre- and even mature miRNAs, respectively. Importantly, whereas most of the mutations did not exert detectable effects on miRNA function, a G --> A mutation at 19 nt downstream of miRNA let-7e led to a significant reduction of its expression in vivo, indicating that miRNA mutation could contribute to tumorigenesis. These data suggest that further screening for genetic variations in miRNA genes from a wide variety of human cancers should increase the discovery and identification of molecular diagnostic and therapeutic targets and complement the mutation analysis of consensus coding sequences in human cancers.
Protein-protein interactions play an important role in the specificity of cellular signaling cascades. By using the yeast two-hybrid system, a specific interaction was identified between the second PDZ domain of the cytosolic protein tyrosine phosphatase hPTP1E and a novel protein, which was termed ZRP-1 to indicate its sequence similarity to the Zyxin protein family. The mRNA encoding this protein is distributed widely in human tissues and contains an open reading frame of 1428 base pairs, predicting a polypeptide of 476 amino acid residues. The deduced protein displays a prolinerich amino-terminal region and three double zinc finger LIM domains at its carboxyl terminus. The specific interaction of this novel protein with the second PDZ domain of hPTP1E was demonstrated both in vitro, using bacterially expressed proteins, and in vivo, by co-immunoprecipitation studies. Deletion analysis indicated that an intact carboxyl terminus is required for its interaction with the second PDZ domain of hPTP1E in the yeast two-hybrid system and suggested that other sequences, including the LIM domains, also participate in the interaction. The genomic organization of the ZRP-1 coding sequence is identical to that of the lipoma preferred partner gene, another Zyxin-related protein, suggesting that the two genes have evolved from a recent gene duplication event.Protein-protein interactions play a crucial role in maintaining the normal function of cells. Such interactions are important in the transmission of signals within the cell. Scaffolding, anchoring, and adaptor proteins, which bring together the various signaling molecules through such interactions, are determinant in fine-tuning these pathways and often contain modular structural domains mediating protein-protein interactions (1-3). A partial list of these domains include Src homology 2 and 3 (SH2 and SH3) domains (4), Tyr(P) binding domains (5), pleckstrin homology domain (6, 7), and PDZ domain (8, 9).PDZ domains consist of a motif of approximately 90 amino acid residues, found in one or multiple copies in a variety of signaling proteins. This domain derives its name from the three proteins originally shown to contain these sequences as follows: post-synaptic density protein, PSD-95 (10), the Drosophila septate junction protein discs-large tumor suppressor, Dlg (11), and the epithelial tight junction protein, ZO-1 (12). Other PDZ domain-containing proteins include nitric oxide synthase (13), the Drosophila dishevelled protein, Dsh (14), the channel-interacting PDZ domain protein (15), etc. (for reviews see Refs. 9 and 16).PDZ domains have also been found in a subfamily of protein tyrosine phosphatases (PTPs), 1 which includes PTPH1 (17), PTPMEG (18), and hPTP1E (19). The latter, also called PTP-BAS, PTPL1, and FAP-1, is a cytosolic PTPase and contains five PDZ domains in addition to a single tyrosine phosphatase catalytic domain. This protein also contains other distinct structural elements including a band 4.1 homology domain and five PEST regions (19 -22). A recent st...
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