Tissue inhibitor of metalloproteinases–1 (TIMP–1) has been shown to be increased in liver fibrosis development both in murine experimental models and human samples. However, the direct role of TIMP–1 during liver fibrosis development has not been defined. To address this issue, we developed transgenic mice overexpressing human TIMP–1 (hTIMP–1) in the liver under control of the albumin promoter/enhancer. A model of CCl₄–induced hepatic fibrosis was used to assess the extent of fibrosis development in TIMP–1 transgenic (TIMP–Tg) mice and control hybrid (Cont) mice. Without any treatment, overexpression of TIMP–1 itself did not induce liver fibrosis. There were no significant differences of pro–(α1)–collagen–I, (α2)–collagen–IV, and α–smooth muscle actin (α–SMA) mRNA expression in the liver between TIMP–Tg and Cont–mice, suggesting that overexpression of TIMP–1 itself did not cause hepatic stellate cell (HSC) activation. After 4–week treatment with CCl₄, however, densitometric analysis revealed that TIMP–Tg–mice had a seven–fold increase in liver fibrosis compared with the Cont–mice. The hepatic hydroxyproline content and serum hyaluronic acid were also significantly increased in TIMP–Tg–mice, whereas CCl₄–induced liver dysfunction was not altered. An active form of matrix metalloproteinases–2 (MMP–2) level in the liver of TIMP–Tg–mice was decreased relative to that in Cont–mice because of the transgenic TIMP–1. Immunohistochemical analysis revealed that collagen–I and collagen–IV accumulation was markedly increased in the liver of CCl₄–treated TIMP–Tg–mice with a pattern similar to that of α–SMA positive cells. These results suggest that TIMP–1 does not by itself result in liver fibrosis, but strongly promotes liver fibrosis development.

We review the evidence in support of the notion that, upon experimental oncogenic transformation or in spontaneous human cancers, mitogenesis and expression of urokinase (uPA) and its receptor (uPAR) are activated through common signaling complexes and pathways. It is well documented that uPA, uPAR or metalloproteinases (MMPs) are overexpressed in tumor cells of mesenchymal or epithelial origin and these molecules are required for tumor invasion and metastasis. Furthermore, oncogenic stimuli, which may render the transformed cells tumorigenic and metastatic in vivo, activate, in a constitutive fashion, the extracellular‐regulated kinases (Erk 1 and 2) classical mitogenic pathway and others such as the NH₂‐Jun‐kinase (Jnk). Cells from human tumors or oncogene‐transformed cells overexpress uPA and uPAR, and also show a sustained activation of the above‐mentioned signaling modules. In this paper we show that the classical mitogenic pathway involving Ras‐Erk, PKC‐Erk or Rac‐JNK, among others, is activated by growth factors or endogenously by oncogenes, and constitutively activates uPA and uPAR expression. All the data obtained from human tumors or experimental systems, incorporated into a general model, indicate that oncogenic stimuli lead to the constitutive activation of mitogenesis and uPA and its receptor expression, through the activation of the same classical and nonclassical signaling complexes and pathways that regulate cell proliferation. We also discuss contrasting points of view. For instance, what governs the differential regulation of mitogenesis and the signal that leads to protease overexpression in a way that allows normal cells during physiological events to respond to growth factors, and proliferate without overexpressing extracellular matrix (ECM) proteases? Or how can cells remodel their microenvironment without proliferating? What restrains benign tumors from overexpressing tumor‐associated proteases when they certainly have the mitogenic signal fully activated? This may occur by the differential regulation of transcriptional programs and recent reports reviewed in this paper may provide an insight into how this occurs at the signaling and transcriptional levels.

Telomerase is the enzyme responsible for maintenance of the length of telomeres by addition of guanine-rich repetitive sequences. Telomerase activity is exhibited in gametes and stem and tumor cells. In human somatic cells, proliferation potential is strictly limited and senescence follows approximately 50-70 cell divisions. In most tumor cells, on the contrary, replication potential is unlimited. The key role in this process of the system of the telomere length maintenance with involvement of telomerase is still poorly studied. Undoubtedly, DNA polymerase is not capable of completely copying DNA at the very ends of chromosomes; therefore, approximately 50 nucleotides are lost during each cell cycle, which results in gradual telomere length shortening. Critically short telomeres cause senescence, following crisis and cell death. However, in tumor cells the system of telomere length maintenance is activated. Much work has been done regarding the complex telomere/telomerase as a unique target, highly specific in cancer cells. Telomeres have additional proteins that regulate the binding of telomerase. Telomerase, also associates with a number of proteins forming the sheltering complex having a central role in telomerase activity. This review focuses on the structure and function of the telomere/telomerase complex and its altered behavior leading to disease, mainly cancer. Although telomerase therapeutics are not approved yet for clinical use, we can assume that based on the promising in vitro and in vivo results and successful clinical trials, it can be predicted that telomerase therapeutics will be utilized soon in the combat against malignancies and degenerative diseases. The active search for modulators is justified, because the telomere/telomerase system is an extremely promising target offering possibilities to decrease or increase the viability of the cell for therapeutic purposes.