Disease relevance of PIWIL1

• Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas [1].
• Expression of hiwi gene in human gastric cancer was associated with proliferation of cancer cells [2].
• We found that the expression ratio of hiwi in normal gastric tissues, atrophic gastritis, intestinal metaplasia and gastric cancers was 10% (5/50), 36% (18/50), 36% (18/50) and 76% (38/50), respectively, which was consistent with precancerous development [2].

High impact information on PIWIL1

• Recently, the members of the Piwi sub-family have been shown to interact with new classes of short regulatory RNAs, Piwi-interacting RNAs (piRNAs) and repeat-associated small interfering RNAs (rasiRNAs), which has implications for developmental processes and introduces a new dimension to the field of RNA silencing [3].
• We previously reported that MIWI, a murine PIWI family member, is required for initiating spermiogenesis, a process that transforms round spermatids into mature sperm [4].
• Particularly, microRNA (miRNA)-mediated translational repression involving PIWI/Argonaute family proteins has been widely recognized as a novel mechanism of gene regulation [4].
• Both, mouse and human Piwil2 genes, members of the piwi gene family, are specifically expressed in testis [5].
• Placing CD34(+) cells into culture conditions that supported differentiation and rapid exit from the stem cell compartment resulted in a loss of hiwi expression by day 5 of a 14-day culture period [6].

Biological context of PIWIL1

• Most recently, we discovered a class of noncoding small RNAs called PIWI-interacting RNAs (piRNAs) that are abundantly expressed during spermiogenesis in a MIWI-dependent fashion [4].
• The transient expression of hiwi in the human leukemia cell line KG1 resulted in a dramatic reduction in cellular proliferation [6].
• Overexpression of hiwi led to programmed cell death of KG1 cells as demonstrated by the Annexin V assay system [6].
• Here we report the molecular characterization of hiwi, a human member of the piwi gene family. hiwi maps to the long arm of chromosome 12, band 12q24.33, a genomic region that displays genetic linkage to the development of testicular germ cell tumors of adolescents and adults (TGCTs), i.e., seminomas and nonseminomas [1].
• Moreover, the suppression of hiwi by antisense or RNAi inhibited the growth of gastric cancer cells and induced cell cycle arrest in G2/M phase [2].

Anatomical context of PIWIL1

• Thus, hiwi is specifically expressed in both normal and malignant spermatogenic cells in a maturation stage-dependent pattern, in which it might function in germ cell proliferation [1].
• In addition, gain of this chromosomal region has been found in some TGCTs. hiwi encodes a 3.6 kb mRNA that is expressed abundantly in the adult testis [1].
• In contrast, deletion of the Piwi domain led to a loss of siRNAs but did not abolish polyribosome association [7].

Associations of PIWIL1 with chemical compounds

• Site-directed mutagenesis of conserved amino acids in the Piwi domain identified arginine 735 as essential for RNAi [7].

Other interactions of PIWIL1

• Both roles appear to be widespread among living eukaryotes and this diversification of function could account for the evolutionary conservation of duplicated Argonaute-Piwi proteins [8].
• These studies suggest that hiwi maybe an important negative developmental regulator, which, in part, underlies the unique biologic properties associated with hematopoietic stem and progenitor cells [6].
• The PIWI domain, a highly conserved motif within Argonaute, has been shown to adopt an RNase H fold critical for the endonuclease cleavage activity of RISC [9].

Analytical, diagnostic and therapeutic context of PIWIL1

• RT-PCR findings demonstrated that hiwi was expressed in different gastric cancer cell lines [2].
• To identify the HIWI protein in gastric cancer, we developed a specific monoclonal antibody against HIWI and immunohistochemistry was performed on various gastric tissues [2].
• For example, African "Pygmies," Philippine "Negritos," and the Hiwi of Venezuela are characterized by relatively fast child-juvenile growth for their adult body size (used as a proxy for energetic availability) [10].

References