Current Signal Transduction Therapy

ISSN: 1574-3624

Current Signal Transduction Therapy
Volume 3, Number 1, January 2008

Contents


Regulation of TGF-β Signaling by SMADs and its Roles in Tissue Fibrosis Pp. 1-6
Hirotaka Fukasawa, Tatsuo Yamamoto, Masatoshi Kitagawa and Akira Hishida
[Abstract]


Estrogen Receptor-Positive and Estrogen Receptor Negative Human Breast Cancer Cells: Regulation of Expression of Cancer-Related Genes by Estradiol and Tamoxifen Pp. 7-21
Xia Yuan, Guojin Liu and Ven Murthy
[Abstract]


Role of Platelet Signaling in Thrombus Stabilization: Potential Therapeutic Implications Pp. 22-54
François Saller, Marc Schapira and Anne Angelillo-Scherrer
[Abstract]


Signal Transduction and Photodynamic Therapy Pp. 55-74
Anatoly B. Uzdensky
[Abstract]




Abstracts


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Regulation of TGF-β Signaling by SMADs and its Roles in Tissue Fibrosis
Hirotaka Fukasawa, Tatsuo Yamamoto, Masatoshi Kitagawa and Akira Hishida

Transforming growth factor-β (TGF-β) is a profibrotic cytokine involved in the accumulation of extracellular matrix proteins and progression of various fibrotic diseases. TGF-β signaling is transmitted predominantly through cell surface serine/threonine kinase receptors to intracellular mediators known as Smads. The inhibitory Smad7 represses TGF-β signaling by interacting with activated TGF-β receptors, and downregulation of Smad7 facilitates the effects of TGF-β via activation of Smad2 and 3, the receptor-regulated Smads. Activated Smad complexes then translocate into the nucleus to regulate target gene transcription in collaboration with specific transcriptional factors, coactivators, and corepressors. Moreover, several factors involved in this pathway are modulated by the ubiquitin-proteasome system. Smad ubiquitination regulatory factors (Smurfs), which are HECT (homologous to E6-AP C-terminus)-type E3 ubiquitin ligases, were recently implicated in regulating the function of Smads in scleroderma and renal fibrosis. In addition, transcriptional corepressors, c-Ski (Sloan-Kettering Institute proto-oncogene) and SnoN (ski-related novel gene N), interact with Smads, and the decreased expression of these proteins also facilitates TGF-β signaling via the Smad proteins. Abnormalities of these regulators of TGF-β signaling may influence organ fibrogenesis, and further studies may reveal new strategies for controlling pathological TGF-β activity.

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Estrogen Receptor-Positive and Estrogen ReceptorNegative Human Breast Cancer Cells: Regulation of Expression of Cancer-Related Genes by Estradiol and Tamoxifen
Xia Yuan, Guojin Liu and Ven Murthy

Breast cancer is one of the most prevalent forms of carcinomas among women world-wide. The oncogenes, tumor suppressor genes and antioxidant enzyme genes are cancer-related genes which play an important role in the initiation, metastasis and malignancy of many cancers, including breast cancer. Estrogen which is a key steroid hormone in the regulation and differentiation of the normal breast also appears to be involved in the carcinogenesis of this tissue. Antiestrogen therapy, such as the use of tamoxifen, targets the estrogen receptors (ER) through which estrogen exerts both its normal biological function as well as the molecular processes leading to cancer formation.

The objectives of the present study were to characterize and quantify the expression of genes related to human breast carcinogenesis, using ER- positive (ZR-75-1) and ER-negative (MDA-MB-231) cells as in vitro cellular models of breast cancer. We have examined the expression of a number of genes which have an important clinical significance in human breast cancer, when expressed at levels below or above the normal range. Among these are the receptor oncogenes (EGFR, c-erbB2), other oncogenes (pS2, hMAM, MUC1 and CK-19), the tumor suppressor gene, p53, as well as four of the major antioxidant enzyme genes. These are superoxide dismutase-1 (SOD1), superoxide dismutase-2 (SOD2), Se-glutathione peroxidase (GPx1) and catalase (CAT), all of which have been well characterized in human cells, and whose activities have been localized to different cellular compartments, such as the cytoplasm, mitochondria and peroxisomes. Gene expressions were determined using real-time PCR, in control untreated cells as well as when these two cell types were exposed to 17β-estradiol (E), or tamoxifen (TAM) or a combination of E and TAM.

Our results show that basal level expressions of receptor oncogenes (EGFR and c-erbB2) as well as two of the four antioxidant enzyme genes (SOD2 and GPx1) were several folds lower in ER-positive breast cancer cells (ZR-75-1) as compared to ER-negative cells (MDA-MB-231). However, treatment with E and TAM, either individually or in combination, produced much greater effects on the ER-positive cells than on the ER-negative cells, with the result that these genes were greatly overexpressed in the ER-positive cells as compared to the ER-negative cells. Of these, the receptor oncogene, c-erbB2, and the antioxidant enzyme gene, SOD2, were the most affected, resulting in striking upregulations ranging over several hundred folds. This, and other observations, would suggest that the carcinogenic effects of estradiol and the anticarcinogenic effects of tamoxifen are not only mediated by the presence of estrogen receptors, but may also be regulated, either directly or indirectly, through other mechanisms, including the mitochondrial antioxidant system.


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Role of Platelet Signaling in Thrombus Stabilization: Potential Therapeutic Implications
François Saller, Marc Schapira and Anne Angelillo-Scherrer

Platelets initiate arrest of bleeding at sites of vascular injury but also trigger inopportune arterial thrombosis, which causes heart attack and stroke. After formation of a single platelet monolayer at the site of injury, additional platelets are recruited into the growing hemostatic plug. Without further stabilization, the platelet plug disaggregates. Its stabilization is ensured by perpetuation of platelet activation. Drugs designed to prevent thrombus stabilization rather than inhibition of its formation, are currently not available. Platelet signaling of the perpetuation phase of platelet activation might represent a potential target for antiplatelet drugs that would prevent thrombosis without eliciting bleeding.


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Signal Transduction and Photodynamic Therapy
Anatoly B. Uzdensky

Photodynamic therapy (PDT), in which stained cells are damaged by light in the presence of oxygen, is now widely used for tumor destruction. Photogenerated singlet oxygen and reactive oxygen species cause oxidative stress and cell death. The potential ROS sensors and following intracellular processes leading to cell death are considered. The cell death mode (necrosis or apoptosis) is shown to be controlled not only by PDT parameters (irradiation intensity, intracellular photosensitizer localization and its concentration) but also by signal transduction processes. Calcium and adenylate cyclase signaling pathways, receptor tyrosine kinases, MAP kinases, phosphatidylinositol 3-kinase pathway, various protein kinases and phosphatases, transcription factors, ceramide, NO, the plasma membrane, mitochondria and endoplasmic reticulum are involved in the cell response to photodynamic injury and following death. Combination of PDT and pharmacological modulators of signaling pathways can either enhance injury of malignant cells, or protect surrounding normal cells.