Stetler-Stevenson et al. (1989) found that a 21-kD protein, which is secreted by human melanoma cells and binds to type IV
collagenase proenzyme secreted by the same cells, has an amino acid sequence with many similarities to human tissue
inhibitor of metalloproteinase. They demonstrated that addition of purified TIMP2 to activated type IV procollagenase resulted in
inhibition of the collagenolytic activity in a stoichiometric fashion.
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. Unlike the inducible expression of some other TIMP gene family members, the expression of this gene is largely constitutive. In addition, this gene diplays several features of a housekeeping gene and is likely to play a role significantly different from that of other family members.
General function
Comment
Cellular localization
Extracellular Matrix, Secreted
Comment
Ovarian function
Ovulation
Comment
Chaffin CL et al elucidated the pattern of
expression and progesterone regulation of mRNAs for the matrix metalloproteinases (MMPs) and their tissue inhibitors
(TIMPs) in macaque granulosa cells during controlled ovarian stimulation cycles before (0 h) and after (up to 36 h)
administration of an ovulatory hCG bolus. Levels of mRNAs for interstitial collagenase, gelatinase A, matrilysin, TIMP-1
and TIMP-2 increased (p < 0.05) within 12 h of hCG, while gelatinase B mRNA increased later, by 36 h after hCG.
Administration of a 3beta-hydroxysteroid dehydrogenase inhibitor (Trilostane [TRL]) during hCG treatment decreased mRNA levels for interstitial collagenase, gelatinase B, matrilysin, TIMP-1, and TIMP-2. Progestin (R5020)
replacement during hCG+TRL treatment returned interstitial collagenase and TIMP-1 mRNAs to control levels. These data
suggest that one action of progesterone, and possibly other steroids, in the cascade of events leading to ovulation and
luteinization of the primate follicle is to regulate the expression of specific ovarian proteases and protease inhibitors.
Expression regulated by
LH, Steroids, progesterone
Comment
Nothnick WB et al assessed the function of TIMP-1 during the periovulatory period in vivo. Twenty-three-day-old TIMP-1-deficient and wild-type female mice were injected with 5 IU eCG, followed 48 h later by an ovulation-inducing dose of hCG (5 IU). Animals were killed at the time of hCG
injection (0-h hCG), at 12 h (12-h hCG), or at 24 h post-hCG (24-h hCG) administration. Serum was collected for the
assessment of estradiol-17beta (0-h hCG groups) or progesterone content (12- and 24-h hCG groups), while ovaries were removed for either histological preparation or Northern analysis of TIMP-1, TIMP-2, and TIMP-3. The number of healthy
and atretic follicles was determined in the 0-h hCG groups, as was the number of oocytes released in the 24-h hCG group.
TIMP-1-deficient females in the 0-h hCG group showed reduced levels of ovarian TIMP-2 (0.29-fold decrease, p < 0.05)
and TIMP-3 (3.0-fold decrease, p < 0.05) expression compared to wild-type counterparts. No significant difference was
detected between genotypes in the 0-h hCG group for number of healthy or atretic follicles or for serum estradiol-17beta
concentrations. Additionally, no significant differences were detected between genotypes in the 12- and 24-h hCG groups for
serum progesterone concentrations, ovarian TIMP-2 and TIMP-3 expression, or number of oocytes released (24-h hCG
group). To assess the effect of TIMP-1 on steroidogenesis in vitro, granulosa cells were obtained from 23-day-old,
eCG-primed TIMP-1-deficient and wild-type females. Addition of recombinant human TIMP-1 significantly increased
conditioned media estradiol-17beta concentrations in cell cultures from both mutant and wild-type females. It is concluded from this study that TIMP-1 may modulate
ovarian TIMP-2 and TIMP-3 mRNA expression during folliculogenesis. In addition, TIMP-1 exhibits steroidogenic activity
in vitro, but no evidence was found for regulation of steroidogenesis in vivo.