No abstract

Estrogens play an important role in regulating the growth and differentiation of normal, premalignant and malignant cell types, especially breast epithelial cells, through interaction with two nuclear estrogen receptors (ER and ERIn this review, we present a brief overview of the actions of estrogens in the different steps of breast carcinogenesis, including cancer progression to metastasis, and of their clinical consequences in the prevention, prognosis and treatment of the disease. The requirement of estrogen receptors, mainly of the alpha subtype, in normal mammary gland differentiation and growth has been evidenced by estrogen receptor deficiency in animals. The promotion of breast cancer carcinogenesis by prolonged exposure to estrogens is well-documented and this has logically led to the use of antiestrogens as potentially chemopreventive agents. In breast cancer progression, however, the exact roles of estrogen receptors have been less well established but they may possibly be dual. Estrogens are mitogenic in ER-positive cells and antiestrogens are an efficient adjuvant therapy for these tumors. On the other hand, the fact that estrogens and their receptors protect against cancer cell invasiveness through distinct mechanisms in experimental models may explain why the presence of ER is associated with well-differentiated and less invasive tumors.2

The AKT2 K ؉ channel is endowed with unique functional properties, being the only weak inward rectifier characterized to date in Arabidopsis. The gene is expressed widely, mainly in the phloem but also at lower levels in leaf epiderm, mesophyll, and guard cells. The AKT2 mRNA level is upregulated by abscisic acid. By screening a two-hybrid cDNA library, we isolated a protein phosphatase 2C (AtPP2CA) involved in abscisic acid signaling as a putative partner of AKT2. We further confirmed the interaction by in vitro binding studies. The expression of AtPP2CA ( ␤ -glucuronidase reporter gene) displayed a pattern largely overlapping that of AKT2 and was upregulated by abscisic acid. Coexpression of AtPP2CA with AKT2 in COS cells and Xenopus laevis oocytes was found to induce both an inhibition of the AKT2 current and an increase of the channel inward rectification. Site-directed mutagenesis and pharmacological analysis revealed that this functional interaction involves AtPP2CA phosphatase activity. Regulation of AKT2 activity by AtPP2CA in planta could allow the control of K ؉ transport and membrane polarization during stress situations. INTRODUCTIONPotassium is the most abundant cation in the cytoplasm of the living cell, where it is involved in the regulation of ionic strength, osmotic potential, and membrane polarization. K ϩ channels of the so-called Shaker family (nine genes in Arabidopsis) have been shown to play a role in K ϩ uptake by the root periphery (AKT1: Lagarde et al., 1996; Hirsch et al., 1998), K ϩ secretion into the root xylem sap (SKOR: Gaymard et al., 1998), K ϩ transport in the phloem tissues (AKT2: Marten et al., 1999;Lacombe et al., 2000), or K ϩ inward (KAT1: Ichida et al., 1997;Szyroki et al., 2001; KAT2: Pilot et al., 2001) and outward (GORK: Ache et al., 2000) fluxes in guard cells, leading to stomatal opening/closing.To adapt to fluctuating K ϩ availability in the environment and to cope with other stresses, plants need to tightly regulate K ϩ transport at both the whole plant and the cell level (Kochian and Lucas, 1988;Schroeder et al., 1994). Studies aimed at revealing the molecular determinants of these regulations have highlighted mechanisms likely to target Shaker K ϩ channels at both the transcriptional and posttranslational levels. Expression studies have revealed that transcript levels of Shaker channels are sensitive to hormones (Gaymard et al., 1998;Philippar et al., 1999;Lacombe et al., 2000), sugar synthesis and accumulation, and environmental signals (Deeken et al., 2000). At the post-translational level, indications have been found for regulation by ATP and cyclic GMP (Hoshi, 1995), phosphorylation events (Li et al., 1994; Armstrong et al., 1995; Tang and Hoshi, 1999), functional interactions with the cytoskeleton (Hwang et al., 1997), 14-3-3 proteins (Saalbach et al., 1997 Booij et al., 1999), sulfonylurea receptors (Leonhardt et al., 1997), syntaxins (Leyman et al., 1999), and G proteins (Wu andWang et al., 2001).Searches for interacting proteins have been focused on t...

Under standard culture conditions, tumor cells are exposed to 20% O(2), whereas the mean tumor oxygen levels within the tumor are much lower. We demonstrate, using low-passaged human tumor cell cultures established from glioma, that a reduction in the oxygen level in these cell cultures dramatically increases the percentage of CD133 expressing cells.