| Laboratory of Ignacio Palmero Rodríguez |
Role of ING4 in intercellular communication during tumorigenesis.
ING proteins are tumor suppressors that act primarily as epigenetic regulators in association with factors such as NF-kappaB and p53. These proteins are involved in various cellular functions important in tumor initiation and progression, such as control of cell division, apoptosis or migration, among others. The loss of ING protein function by diverse mechanisms, is frequent in human tumors. To understand the role in tumorigenesis of ING4, one of the ING family members, we have recently analyzed ING4 function in primary non-tumor fibroblasts, which retain intact tumor suppressor mechanisms. Our results indicate that ING4 displays a p53-dependent antiproliferative effect in these cells. By analyzing the gene expression changes associated with ING4, we found that ING4 regulates a complex secretome in primary cells, that has dual effects on proliferation, inhibiting the proliferation of non-tumor primary cells, but promoting the proliferation of tumor cells and their ability to form tumors in immunodeficient mice (Moreno et al., submitted). Taken together, our results indicate that ING4 regulates not only the proliferation of human non-transformed fibroblasts, but also controls a secretory phenotype in these cells, which promotes tumor cell proliferation in vitro and in vivo. These results support a critical role of ING4 in communication between tumor cells and their environment, with implications for tumor growth.
Role of ING1 in cellular senescence
Cellular senescence is an anti-proliferative response that acts as an effective barrier to tumor formation in vivo. We have investigated the role of the tumor suppressor p33ING1 in the regulation of senescence in human primary fibroblasts (Abad et al, 2011). We have found that p33ING1 accumulates in chromatin during oncogene-induced senescence, and its silencing blocks this response. Furthermore, ectopic expression of p33ING1 triggers a senescent phenotype in this cell type, dependent on p53 and chromatin marks recognition, and this effect is absent in a tumor-associated mutant version of p33ING1. Finally, induction of senescence by ING1 is associated with a specific genetic signature with strong representation of chemokines and cytokines, characteristic of the secretory phenotype associated with senescence (SASP). In summary, our results have identified ING1 as an essential epigenetic regulator of cellular senescence and have revealed its role in the control of gene expression in the context of this anti-tumor protection response (Menendez et al, 2009; Abad et al , 2011).
Ing1 as a melanoma suppressor gene.
We are using animals deficient for the Ing1 locus (Abad et al., 2007) to understand the role of this locus in tumorigenesis in vivo. Using a mouse model of melanoma predisposition (Tyr:NRASQ61K mice), we found that ING1 deficiency increases the incidence and reduces the latency of melanoma in these animals, and also increases their ability to metastasize. This effect in Ing1-deficient animals is associated with the retention in tumors of p19Arf, a suppressor gene linked to p53, normally inactivated in mouse melanoma. These data suggest an important role for ING1 as a melanoma suppressor gene, in connection with the Arf-p53 tumor suppressor pathway (Menendez et al, submitted).
microRNAs biogenesis and senescence.
We have observed that the perturbation of microRNA biogenesis in primary fibroblasts results in a proliferative response accompanied by the acquisition of a senescent phenotype. Senescence induced by the loss of DGCR8, an essential mediator of canonical miRNAs synthesis, is accompanied by the induction of the cell cycle inhibitor p21Cip1. Furthermore, a group of senescence-associated miRNAs linked to regulation of p21Cip1 are repressed during DGCR8 mediated senescence. This antiproliferative response to the disruption of miRNA biogenesis is retained in tumor cells, regardless of p53 status. In summary, our results identify the disruption of the biogenesis of miRNAs as a new pro-senescent stimulus and reveal the existence of a pathway regulatory of senescence that involves miRNAs and cell cycle regulators (Gomez-Cabello et al, submitted).