Biomedical subjects

Raquel Blanco

Publications and source records attributed to Raquel Blanco.

4 recordsLinked to original sources

PubMed2006

Role of the TRF2 telomeric protein in cancer and ageing.

Telomeres are the special heterochromatin that forms the ends of chromosomes, consisting of TTAGGG repeats and associated proteins. Telomeres protect the ends from degradation and recombination, and are essential for chromosomal stability. Both a minimal length of telomere repeats and the telomere-binding proteins are required for telomere protection. Telomerase is a DNA polymerase that specifically elongates telomeres, in this way regulating telomere length and function. A minimal telomere length is required to maintain tissue homeostasis. On one hand, critically short telomeres trigger loss of cell viability and premature death in mice deficient for telomerase activity. Furthermore, altered functioning of telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and cancer. A new mouse model with critically short telomeres has been generated by overexpressing the TRF2 telomere-binding protein, K5-TRF2 mice. These mice show short telomeres in the presence of telomerase activity, leading to premature aging and increased cancer. Short telomeres in TRF2 mice can be rescued in the absence of the XPF nuclease, indicating that this enzyme rapidly degrades telomeres in the presence of increased TRF2 expression. K5-TRF2 mice represent a new tool to understand the consequences of critical telomere shortening a telomerase-proficient genetic background, more closely resembling human cancer and aging pathologies.

Aging↗

PubMed2005

XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer.

TRF2 is a telomere-binding protein that has a role in telomere protection. We generated mice that overexpress TRF2 in the skin. These mice had a severe phenotype in the skin in response to light, consisting of premature skin deterioration, hyperpigmentation and increased skin cancer, which resembles the human syndrome xeroderma pigmentosum. Keratinocytes from these mice were hypersensitive to ultraviolet irradiation and DNA crosslinking agents. The skin cells of these mice had marked telomere shortening, loss of the telomeric G-strand overhang and increased chromosomal instability. Telomere loss in these mice was mediated by XPF, a structure-specific nuclease involved in ultraviolet-induced damage repair and mutated in individuals with xeroderma pigmentosum. These findings suggest that TRF2 provides a crucial link between telomere function and ultraviolet-induced damage repair, whose alteration underlies genomic instability, cancer and aging. Finally, we show that a number of human skin tumors have increased expression of TRF2, further highlighting a role for TRF2 in skin cancer.

Aging, Premature↗

PubMed2005

[Genotypic resistence in patients infected with HIV and its correlation with therapy].

BACKGROUND AND OBJECTIVE: Our goal was to establish the different therapeutic regimens used in our clinical setting, and to determine the prevalence of genotypic resistances in patients under antiretroviral therapy, analyzing the relationship between the appearance of mutations and treatments along with other HIV related variables. MATERIAL AND METHOD: 191 samples from the same number of patients who were on antiretroviral therapy and virological failure were analyzed. Samples were processed by means of the genotypic technique LiPA in order to study the presence of mutations in the reverse transcriptase (RT) and the protease (P) genes. Prescribed therapeutic regimens and epidemiological variables relevant in HIV infection were also analyzed. RESULTS: Overall resistance prevalence was 72.32%. By LiPA, RT mutations were detected in 71.43% of patients, being M184V, T215Y and L41M the most frequent ones. Moreover, P mutations were detected in 59.38% of cases, being V82A, L90M and I84V the most frequent ones. 61.02% of the patients presented one or more mutations against the reverse transcriptase inhibitors included in their treatment. With regard to protease inhibitors, this fact was documented in 28.81% of cases, and in 23.73% of patients receiving both reverse transcriptase inhibitors and protease inhibitors. CONCLUSIONS: Although the analysis of the mutation patterns by LiPA has known limitations, the prevalence of resistances in our study was different from that reported by other authors, being lower in the P gene and higher in the RT one. Of note, a high proportion of patients showed mutations against the drugs included in their prescribed treatment.

Drug Resistance, Viral↗

PubMed2002

Cell killing by HIV-1 protease.

The human immunodeficiency virus protease (HIV-1 PR) was expressed both in the yeast Saccharomyces cerevisiae and in mammalian cells. Inducible expression of HIV-1 PR arrested yeast growth, which was followed by cell lysis. The lytic phenotype included loss of plasma membrane integrity and cell wall breakage leading to the release of cell content to the medium. Given that neither poliovirus 2A protease nor 2BC protein, both being highly toxic for S. cerevisiae, were able to produce similar effects, it seems that this lytic phenotype is specific of HIV-1 PR. Drastic alterations in membrane permeability preceded the lysis in yeast expressing HIV-1 PR. Cell killing and lysis provoked by HIV-1 PR were also observed in mammalian cells. Thus, COS7 cells expressing the protease showed increased plasma membrane permeability and underwent lysis by necrosis with no signs of apoptosis. Strikingly, the morphological alterations induced by HIV-1 PR in yeast and mammalian cells were similar in many aspects. To our knowledge, this is the first report of a viral protein with such an activity. These findings contribute to the present knowledge on HIV-1-induced cytopathogenesis.

Animals↗