High-temperature requirement factor A3 (Htra3): A novel serine protease and its potential role in ovarian function and ovarian cancers

The high-temperature requirement factor A (Htra) family of serine proteases is conserved from bacteria to humans. In the mouse and human, Htra3, a member of the Htra family, is transcribed into two transcripts through alternative splicing. In the rat, Htra3 is located on chromosome 14q21 and the overall intron/exon structure of Htra3 is conserved between the rat, mouse and human. Rat Htra3, similar to the mouse and human, is alternatively spliced into two transcripts (long and short). The expression and regulation of Htra3 gene and protein in the rat ovary was recently determined. The long form Htra3 has the dominant expression throughout rat ovarian postnatal development, folliculogenesis and luteinization compared to short form Htra3. The expression of the HTRA3 gene and the cellular localization of the protein in the rhesus monkey ovary were investigated. Protein expression increased during folliculogenesis and was significantly higher in the granulosa-lutein cells compared to the theca-lutein cells, suggesting a role for HTRA3 in folliculogenesis and luteinization in the primate ovary. A preliminary study has also revealed a significant decrease in HTRA3 mRNA expression in ovarian cancer and granulosa cell tumor cell lines, suggesting that HTRA3 may act as a tumor suppressor. The role of the PDZ domain, specific to the long form Htra3, and the specific substrates of Htra3 in vivo, need to be defined to better understand the roles of HtrA3 in the normal and malignant ovary.