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CELL
DIFFERENTIATION
AND
DEVELOPMENT OF
CELL
MODELS |
MEMBERS
AND COLLABORATORS
Name |
Category |
E-mail |
Carmen Marín Vieira (Coord) |
TU ULE |
carmen.marin@unileon.es |
Inmaculada Diez
Prieto |
TU
ULE |
idiep@unileon.es |
María José Cano
Rábano |
TU
ULE |
maria.cano@unileon.es |
Margarita Marqués
Martínez |
PCD ULE |
mmarm@unileon.es |
Alfonso Fernández
Corona |
Jefe Sección Obs/GinecologíaCAULE |
alfonsofernandezcorona@yahoo.es |
Mª Elena Lorenzo
Marcos |
Licen. Especial. Obs/Ginecología
CAULE |
eleloma@yahoo.es |
Marta Martín López |
Becaria JCyL |
marta.martin@unileon.es |
Sandra Fuertes Alvarez |
Becaria JCyL |
sfuea@unileon.es |
OBJECTIVES
1.
Generation and development of in vitro differentiation models
from stem cells (mESC, ASC and iPSC) and its applications for drug
screening. |
2.
Development of in vitro angoigenic assays. |
3. Study of the molecular mechanisms that regulate stem cell
pluripotency and differentiation. |
4.
Study of the role of the p53 family members in stem cell biology. |
ACTIVITIES
Our research focuses in investigating the role of p53 family members in stem
cell biology and cell differentiation. For this purpose, we use mouse
embryonic stem cells (mESC) as well as adult stem cells, with particular
interest in neural stem cells. Recently, we have generated induced
pluripotent stem cells (iPSC) from embryonic fibroblasts derived from
genetically modified mice (p53KO y p73KO) (Martin-Lopez et al., in
preparation).
The p53 gene family is constituted by the transcription factors p53, p73 and
p63. Despite their sequence homology, the p53 family members possess both
common as well as non-overlapping functions. There is evidence that suggest
that p73 maintains some unique functions not shared with p53, like the
p73-specific role in cellular differentiation and development. We have
demonstrated that p73 function is necessary for neural differentiation
mediated by Ras, showing for the first time that there is a signaling loop
between Ras-dependent MAPK cascade activation and p73 function (Fernandez et
al., 2006). We have also shown that p73 plays a critical role in erythroid
differentiation (Marqués-García et al., 2009). Moreover, our recent work
using 2D and 3D mESC differentiation models, demonstrates that p73
functional inhibition attenuates endothelial differentiation, impairs
vascular morphogenesis and sprouting, pointing out p73 as an important
player in the regulation of endothelial cell differentiation and
angiogenesis (Fernandez-Alonso et al., in preparation).
Stem cells have triggered a revolutionary progress in analyzing gene
function in vitro. Increasing evidence suggests that signaling pathways and
properties associated with stem cells are important in the development of
certain diseases. Therefore, investigation of the cellular and molecular
mechanisms involved in stem cell biology (self-renewal, pluripotency,
differentiation) could be very valuable to understand disease pathogenesis
and, in some cases, to develop suitable treatments. In addition, the new
advances which allow the restoration of cell pluripotency by the ectopic
co-expression of reprogramming factors in somatic cells, have provided
powerful opportunities for modelling human diseases and new possibilities
for personalized regenerative cell therapies. In this regard, we have
identified TP73 as a positive regulator of self-renewal of neural progenitor
cells, with a role in the maintenance of the neurogenic capacity
(Gonzalez-Cano et al., 2010). These results propose p73 as an important
player in the development of neurodegenerative diseases and a potential
therapeutic target. Furthermore, recent work in our laboratory has
demonstrated the functional interaction between p73 and the neuronal fate
determinant, TRIM32. Our data revealed the existence of a regulatory
feed-back loop between TAp73 and TRIM32, similar to that of p53 and MDM2,
with important implication in physiological processes, and probably in
diseases like Parkinson or cancer (Gonzalez-Cano et al., 2013).
We are also interested in adapting the established cellular models for the
screening of pharmacologically relevant compounds.
Financial support:
National Funding (Spanish Ministry of Science)
-
Functional interaction between p73 and p53 in the regulation of stem
cells self-renewal and pluripotency, and in the process of cellular
reprogramming. 2012-2015.
-
Determination of TP73 functions in the biology of hematopoietic and
neural stem cells. 2009-2012.
-
Study of the cross-talk between Ras and p73: consequences in the
processes of senescence, differentiation and chemosensitivity.
2006-2009.
-
P73 function in processes of neuronal differentiation anad apoptosis.
“Cross-talk” with cell cycle regulators E2F and Myc. 2002-2005
Regional Funding
-
Study of the coordinated functions of TP53 and TP73 tumor suppresors in
the biology of neural stem cells. Relevance to aging and
neurodegenerative diseases. 2010-2012.
-
Analysis of the functional inhibition of p53 family members in mouse
embryonic stem cells: effect on differentiation and response to
genotoxic damage. 2007-2010
-
Study of the role of p53 family members on the maintenance of genomic
stability and differentiation capacity of murine embryonic stem cells.
2006-2008.
-
Study of bimodal function of p73 isoforms in myeloid leukemia.
2005-2006.
Participation in R&D programs with companies
-
Innovative
solutions to accelerate the identification and development of new drugs
for the treatment of diseases of the nervous system. 2011-2013.
-
Development and
validation of new screening procedures for the identification of
candidates to pharmaceuticals from a natural product collection.
2007-2008.
-
Study of the
pharmacological properties of new antitumoral compounds of sea origin.
2005-2006.
-
Study of DNp73
function in chemosensitivity using mouse cancer models. 2005.
TECHNOLOGICAL OFFER
1.
Development of cellular model systems to study cell differentiation
and to utilize them for the screening of pharmacologically relevant
compounds |
SELECTED PUBLICATIONS
-
Gonzalez–Cano, L.; Hillje, A.L., Fuertes-Alvarez, S., Marques, M.M,
Blanch, A., Ian, R.W., Irwin, M.S., Schwamborn, J. & Marin, M.C. (2013).
Regulatory feedback loop between TP73 and TRIM32. Cell Death and
Disease, 4, e704.
-
Gonzalez-Cano.L.,
Herreros-Villanueva, M., Fernandez-Alonso, R., Ayuso-Sacido, A., Garcia-Verdugo,
J.M., Silva, A., Marques, M.M. & Marin, M.C. (2010). p73 deficiency
results in impaired self-renewal and premature neuronal differentiation
of mouse neural progenitors independently of p53.
Cell
Death and Disease, 1, e109.
-
Marques-García, F., Ferrandiz, N., Fernandez-Alonso, R., Gonzalez-Cano,
L., Herreros-Villanueva, M., Rosa-Garrido, M., Fernandez-Garcia, B.,
Vaque, J.P., Marques, M.M., Leon, J. & Marin, M.C. (2009). p73 plays a
role in erythroid differentiation. Journal of Biological Chemistry,
248, 21139 - 21156.
-
Fernandez-Garcia, B., Vaque, J.P., Herreros-Villanueva, M.,
Marques-García, F., Castrillo, F., Fernandez-Medarde, A., Leon, J. &
Marín, M.C. (2007). p73 cooperates with Ras in the activation of MAP
kinase signaling cascade.
Cell Death
Differentiation,
14: 254-265.
-
Fernandez-Alonso. R., Martin-Lopez, M., Gonzalez-Cano L., Garcia- S.,
Diaz-Prieto I., Claesson-Welsh L., Marques, M.M. & Marin, M.C. TP73 is
required for endothelial cell differentiation, migration and the
formation of vascular networks (submitted) .
-
Martin-Lopez, M., Marques, M.M., Navarro-Montero, O., Fuertes-Alvarez,
S., Balboa-Alonso, D., Weltner, J., Menendez-Bujan, P. & Marin, M.C.
Effect of p73 deficiency on somatic cell reprogramming (in
preparation) .
CONTACT
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