Appendix - CNIC

SCIENTIFIC REPORT ´09
Stem cell aging
> RESEARCH INTEREST
The INK4b-ARF-INK4a locus encodes three tumor
suppressors, p15INK4b, ARF, and p16INK4a. Together,
these factors constitute one the most important sources of
cancer protection in mammals, equalled in importance only
by p53. These tumor suppressors have taken on additional
importance in the light of recent evidence that at least one
product of the locus, p16INK4a, also contributes to the
decline in the replicative potential of self-renewing cells with
age. Thus, on the one hand, p16INK4a promotes longevity
through its action as a potent tumor suppressor, while on the
other hand the increased expression of p16INK4a with age
reduces stem and progenitor cell proliferation, ultimately
reducing longevity. In other words, p16INK4a appears to
balance the need to prevent cancer against the need to
> MAJOR GRANTS
Head of Laboratory: Susana Gonzalez
Postdoctoral Researchers: Celia Cerrato Rivera
Technicians: Pilar Mendoza Doroca
Christian Torrenteras Ruano
Cristiana de Jesús Oliveira Leite
Antonio Herrara Merchán
Ma Eugenia Alonso Ferrero
Antonio José Montes Ruiz
- Human Frontier Science Program Organization
(HFSPO). Career Development Award
- Ministerio de Ciencia e Innovación. FIS (PI060627)
SELECTED PUBLICATIONS
27
2 Regenerative Cardiology
sustain regenerative capacity throughout life. These
observations suggest the provocative but unproven notion
that mammalian aging results in part from the effectiveness
of tumor suppressor proteins at preventing cancer.
Our group is investigating the role and molecular regulation
of the INK4b-ARF-INK4a locus in the context of selfrenewal,
proliferation and aging of hematopoietic stem cells
in vitro and in vivo, with planned extension of these studies
to cardiac stem cells. In parallel, we are developing tools for
the study of the genetic and epigenetic mechanisms that
regulate stem cells, and how these unique cells differentiate
from a pluripotent to a more restricted state.
The INK4/ARF locus regulates cancer
cell proliferation and stem cell aging, and in
this way may control the balance between the
needs for regenerative capacity and for
protection against the increased risk of
neoplasms with age.
Gonzalez S, Pisano D, Serrano M. Mechanistic principles of chromatin remodeling guided by siRNAs and miRNAs. Cell Cycle (2008)
7: 2601-8
Benetti R, Gonzalo S, Jaco I, Munoz P, Gonzalez S, Schoeftner S, Murchison E, Andl T, Chen T, Klatt P, Li E, Serrano M, Millar S,
Hannon G, Blasco MA. A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent
regulation of DNA methyltransferases. Nat Struct Mol Biol. (2008) 15: 268-79
de Yebenes VG, Belver L, Pisano DG, Gonzalez S, Villasante A, Croce C, He L , Ramiro AR. miR-181b negatively regulates activationinduced
cytidine deaminase in B cells. J Exp Med (2008) 205: 2199-206