| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Matrix metalloproteinase-23 (MMP-23), expressed predominantly in ovary and uterus, belongs to the MMP family that has been known to play a certain role in degrading and remodeling components of extracellular matrix (ECM). However, the physiological function of MMP-23 in the female reproductive organs remains yet to be clarified. During maturation of the follicle development in response to gonadotropin surge, expression levels of MMP-23 in granulosa cells were controlled under the state of differentiation of follicles. In the healthy follicles MMP-23 expression was repressed depending on the intracellular levels of cAMP, whereas, in the atretic follicles gene expression of MMP-23 was induced via de novo protein synthesis. When endogenous A-kinase or Akt expression was suppressed with the small interference RNA (siRNA) against rat A-kinase and Akt, gene repression of MMP-23 by cAMP was significantly inhibited. This result indicates the both kinases, activated by cAMP, are involved in the
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gene regulation of MMP-23 in the rat granulosa cells. Analysis of 1.5kb of the 5-flanking DNA sequence in the rat MMP-23 gene promoter revealed the absence of TATA box and Ets sequence in contrast to the other MMP family promoters. Detailed analysis of this promoter region has been under investigating to reveal the putative regulatory elements for cAMP-dependent repression and apotosis-dependent increment of MMP-23 gene expression.
To identify the physiological substrates for MMP-23 in the ovary, yeast two hybrid screening was carried out with human ovarian cDNA library using the catalytic domain of MMP-23 as a bait. As a result, interactive candidates were isolated including the ECM (fibronectin and fibrillin) and LTBP (latent TGF-β binding protein). From the binding analysis, MMP-23 interacts with fibrillin and LTBP via their EGF-like modules. TGF-β has been known as an indispensable factor for regulating the follicle maturation and active TGF-β must be released from the large complex of LTBP and ECM to exert its functions. Therefore, these results raise the possibility that MMP-23 might play a role in regulating the level of active TGF-β through modulating the ECM and LTBP in the ovarian follicles. Less
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