Download SEMINARIO 1 de marzo de 2013, 12:30 Insttuto

Arantxa Tabernero
Instituto de Neurociencias de Castilla y León (INCYL)
Universidad de Salamanca. Salamanca. Spain
SEMINARIO
1 de marzo de 2013, 12:30
Insttuto Cajal. CSIC
Avda. Dr. Arce, 37. Madrid
Disruption of connexin43 gap junctional communication in gliomas and other CNS
pathologies
Connexin43 (Cx43), the most abundant connexin in mammals, is an integral membrane protein widely expressed in
different tissues. In the CNS, Cx43 is strongly expressed in astrocytes where it exerts a variety of important biological
functions. Cx43 assembles to form gap junction channels that facilitate the behavior of astrocytes as metabolic
networks. Furthermore, the intracellular carboxy tail of Cx43 interacts with a large number of signaling and scaffolding
proteins, thereby regulating cell functions such as cell adhesion, migration and proliferation. Thus, a decrease in Cx43
expression is usually observed in gliomas and the levels of this protein are inversely correlated with their degree of
malignancy. Interestingly, restoring Cx43 in glioma cells reduces their rate of proliferation. Our results showed that by
acting as a substrate of c-Src, Cx43 reduces c-Src activity and decreases the rate of glioma cell proliferation. Although
the ability of c-Src to phosphorylate Cx43 and inhibit gap junctional intercellular communication is well known, our study
suggests that Cx43 and c-Src are mutually regulated by a phosphorylation/dephosphorylation loop. Since the activity of
c-Src is specifically elevated in malignant gliomas, our results showing that Cx43 inhibits the strong oncogenic activity of
c-Src could help to design new therapies against gliomas. In addition to gliomas, Cx43 can be modified in reactive
astrocytes. Indeed, in diverse brain pathologies astrocytes become reactive and undergo profound phenotypic changes,
including the expression of Cx43. Down-regulation of Cx43 in cultured astrocytes activates c-Src, promotes proliferation
and increases the rate of glucose uptake. We analyzed this pathway after a cortical lesion induced by a kainic acid
injection in mice. We found that some of the reactive astrocytes proliferate, show reduced levels of Cx43 and increased
activity of c-Src. In addition, the expression of the glucose transporter GLUT-3 and the enzyme responsible for glucose
phosphorylation, type II hexokinase, are induced in some reactive astrocytes, suggesting an increased glucose uptake.
Since glucose taken up by astrocytes is used not only by astrocytes but also to supply the neurons with metabolic
substrates, the increase in the rate of glucose uptake could be a relevant astroglial reaction to promote neuronal
survival. Altogether these data contribute to unravel the signaling pathway related to Cx43 in a variety of CNS
pathologies and may help in the search for new therapeutic targets.
Selected publications:
Reduced connexin43 expression correlates with c-Src activation, proliferation and glucose uptake in reactive astrocytes
after an excitotoxic insult. Ester Gangoso, Pascal Ezan, José Carlos Valle-Casuso, Sandra Herrero-González,
Annette Koulakoff, José M Medina, Christian Giaume and Arantxa Tabernero. (2012) Glia. 60:2040–2049.
HIF-1 and c-Src mediate increased glucose uptake induced by endothelin-1 and connexin43 in astrocytes. José Carlos
Valle-Casuso, Ana González-Sánchez, José M Medina and Arantxa Tabernero. ( 2 0 1 2 ) PLoS One
2012;7(2):e32448.
Connexin43 inhibits the oncogenic activity of c-Src in C6 glioma cells. Sandra Herrero-González, Ester Gangoso,
Christian Giaume, Christian C. Naus, Jose M Medina and Arantxa Tabernero. (2010) Oncogene. 29: 5712–5723.
Inhibition of ATP-sensitive potassium channels increases HSV- tk/GCV bystander effect in U373 human glioma cells by
enhancing gap junctional intercellular communication. Teresa Paíno, Ester Gangoso, Jose M Medina and Arantxa
Tabernero. (2010). Neuropharmacology. 59: 480-491
Sandra Herrero-González, José Carlos Valle-Casuso, Rosa Sánchez-Alvarez, Christian Giaume, José M. Medina and
Arantxa Tabernero. (2009). Connexin43 is involved in the effect of endothelin-1 on astrocyte proliferation and
glucose uptake. Glia 57: 222-233.
Tabernero A., Medina J.M. and Giaume C. (2006). Glucose metabolism and proliferation in glia: role of astrocytic gap
junctions. Journal of Neurochemistry. 99: 1049-1061.
Giaume C., Tabernero A. y Medina J.M. (1997) Metabolic trafficking through astrocytic gap junctions. Glia 21, 114-123.
Tabernero A., Giaume C. y Medina J.M. (1996) Endothelin-1 regulates glucose utilization in cultured rat astrocytes by
controlling intercellular communication through gap junctions. Glia 16, 187-195.