The tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs), a group of peptidases
involved in degradation of the extracellular matrix. Leco KJ have isolated cDNA clones corresponding to a new member of the murine tissue inhibitor of metalloproteinase (TIMP)
family, designated Timp-4. The nucleotide sequence predicts a protein of 22,609 Da that contains the characteristic 12
cysteine TIMP signature. TIMP-4 is more closely related to TIMP-2 and TIMP-3 than to TIMP-1 (48%, 45% and 38%
identity, respectively). Analysis of Timp-4 mRNA expression in adult mouse tissues indicated a 1.2 kb transcript in brain,
heart, ovary and skeletal muscle. Greene et al. (1996) also identified a human EST with homology to known TIMP
sequences and cloned the corresponding gene from a human heart cDNA library. The cDNA encodes a 224-amino acid
polypeptide 37% similar to TIMP1 and 51% similar to TIMP2 and TIMP3. It is unclear whether the human gene is homologous to the mouse one.
NCBI Summary:
This gene belongs to the TIMP gene family. The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix. The protein encoded by this gene may function in a tissue-specific fashion in extracellular matrix homeostasis.
General function
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Cellular localization
Extracellular Matrix, Secreted
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Ovarian function
Luteinization
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Expression regulated by
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Ovarian localization
Luteal cells, Stromal cells, Ovarian tumor
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Localization and temporal regulation of tissue inhibitor of metalloproteinases-4 in mouse ovary. Bu S et al. Tissue inhibitors of metalloproteinases (TIMPs) are potential regulators of tissue remodeling in the ovary. The aim of the present study was to examine the localization and temporal regulation of TIMP-4 protein in the mouse ovary. An induced superovulation model (eCG/hCG) was employed in immature mice to evaluate TIMP-4 protein expression profiles in ovaries collected during the follicular phase, the pre ovulatory period, and the luteal lifespan. Immunofluorescence results indicated that TIMP-4 protein was localized to theca of both antral and preovulatory follicles and adjacent ovarian stroma. After the initiation of luteinization with hCG, TIMP-4 was observed within the luteinizing granulosa cells and persisted throughout the lifespan of the corpus luteum. In the cycling ovary, TIMP-4 signaling localized to corpus luteum from previous estrous cycles, the theca of preovulatory follicles, and appeared to be lower in newly forming corpus luteum. Western analysis further showed that the levels of TIMP-4 increased significantly during the luteinization process of granulosa cells, but no significant change was found among all corpus luteum stages. A putative regulatory mechanism of TIMP-4 expression was identified utilizing an in vitro model. Treatment of cultured granulosa cells with hCG significantly augmented TIMP-4 protein expression levels. Together our data indicate that the luteinization process of granulosa cells is associated with up-regulation of TIMP-4 and that TIMP-4 might play an essential role in maintenance of the luteal function during the whole lifespan of corpus luteum.
Expression of matrix metalloproteinase-26 and tissue inhibitors of metalloproteinase-3 and -4 in normal ovary and ovarian carcinoma. Ripley D et al. The objective of this study was to determine the spatial expression of matrix metalloproteinases (MMPs) and their physiologic inhibitors, the tissue inhibitor of MMP (TIMP)-3 and TIMP-4, in ovarian carcinoma compared to normal ovaries. Immunohistochemistry was carried out in this study. Tissue sections prepared from normal ovarian tissues from throughout the menstrual cycle (N= 20) and ovarian carcinomas (N= 45) characterized as stage I (N= 5), stage III/IV (N= 40) were immunostained using polyclonal antibodies to the latent and the active form of MMP-26, TIMP-3, and a monoclonal antibody to TIMP-4. Immunoreactive MMP-26, TIMP-3, and TIMP-4 were detected in all the ovarian cell types in normal and tumor tissues. In normal ovarian tissues, theca externa and luteal cells immunostained with high intensity for MMP-26 and TIMPs while theca/granulosa cell staining intensity increased as lutenization progressed. There was low immunostaining of the ovarian stromal and surface epithelial cells for MMP-26, with moderate staining for TIMPs. In the carcinoma specimens, cancer cells and vascular endothelial cells displayed the highest staining intensity compared to adjacent nontumor areas. The immunostaining intensity of MMP-26 and TIMP-3 increased with stage of tumor with the invading tumor cells displaying the strongest immunostaining. MMP-26, TIMP-3, and TIMP-4 are expressed in normal ovarian as well as ovarian tumors with elevated expression in the invasive tumor cells suggesting a potential role for MMP-26 in normal ovary and ovarian cancer biologic function.
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Rahkonen OP, et al reported the characterization of the murine Timp4 gene, localization within intron 5 of the synapsin 2 gene and tissue distribution of the mRNA.
The highest levels of TIMP-4 mRNA were seen in postnatal mouse heart, ovary and brain. Determination of the spatial expression pattern of TIMP-4 mRNA by in situ hybridization in the heart revealed a diffuse distribution in cardiac muscle cells. In the ovary, cyclic variation was observed in TIMP-4 mRNA levels. In situ hybridization demonstrated the strongest expression of TIMP-4 mRNA in the corpus luteum. The data suggest that TIMP-4 plays a role in the normal physiology of the heart and the ovary, most likely related to maintenance of the delicate balance between MMPs and TIMPs.