NEW YORK (Reuters Health) - Overexpression of a recently characterized gene called "hiwi" is associated with the development of seminomas in men, according to a new report. Interestingly, findings from another study by the same research team suggest that underexpression of the gene may cause sterility.

In 1997, Dr. Haifan Lin, from Duke University Medical Center in Durham, North Carolina, and colleagues from there and elsewhere, discovered a family of genes that appeared to play a critical role in stem cell division and other developmental processes. Furthermore, the gene family, known as piwi, was found to be present in a broad range of organisms. In 1998, hiwi, a human member of the family, was isolated from a testis cDNA library.

In a study reported in the June 6th issue of Oncogene, Dr. Lin's team describes the molecular characterization of hiwi. The gene was found to reside on chromosome 12 in a region previously linked to the development of testicular germ cell tumors. The HIWI protein was found to be essentially identical to its counterpart MIWI isolated from mice.

The researchers found that hiwi expression was only detectable in normal human testicular cells during spermatogenesis. No hiwi expression was observed in cells from tumors of somatic origin.

In contrast, in 12 of 19 seminoma samples, the tumor cells demonstrated enhanced hiwi expression. Tumors that originated from the same precursor cells as seminomas but later lost their germ cell characteristics did not show enhanced expression. Also, spermatocytic seminomas did not demonstrate enhanced expression.

"This is the first time a strong correlation has been made between seminoma and a particular gene," Dr. Lin told Reuters Health. "In the short term, this gene could be used as diagnostic tool for seminoma," he said. "In the long term, if ethics and policy issues allow, I think hiwi could become a viable target for gene therapy."

In the second study, Dr. Lin and Dr. Wei Deng assessed the effects of miwi deletion in mice. Miwi was found to encode a cytoplasmic protein necessary for spermatogenesis. In mice lacking miwi, spermatogenesis was arrested at the beginning round spermatid stage, rendering the animals infertile. The study's findings are reported in the June issue of Developmental Cell.

The MIWI protein appeared to indirectly interact with the CREM protein, considered the master regulator of spermiogenesis. Specifically, MIWI appeared to regulate the stability of CREM activator mRNAs and CREM target gene mRNAs. Thus, MIWI affects CREM activity by indirectly influencing CREM expression and by modifying CREM's potency once it is generated.

"The next logical step is to determine if infertile men demonstrate decreased hiwi expression," Dr. Lin noted. "Given that hiwi is so similar to miwi, I expect that decreased expression will correlate with infertility in humans," he added. "If this proves to be true, once again, I think gene therapy could offer a solution."

Oncogene 2002. http://www.naturesj.com/onc/

Dev Cell 2002. http://www.developmentalcell.com/

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