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Biomedical subjects

M Serrano

Publications and source records attributed to M Serrano.

At least 19 recordsLinked to original sources
PubMed2001

Thermodynamically consistent mesoscopic fluid particle model.

We present a finite volume Lagrangian discretization of the continuum equations of hydrodynamics through the Voronoi tessellation. We then show that a slight modification of these discrete equations satisfies the first and second laws of thermodynamics. This is done by casting the model into the GENERIC structure. The GENERIC structure ensures thermodynamic consistency and allows for the introduction of correct thermal fluctuations in simple terms. In this way, we obtain a consistent discrete model for Lagrangian fluctuating hydrodynamics. Simulation results are presented that show the validity of the model for simulating hydrodynamic problems at mesoscopic scales.

Journal Article↗
PubMed2001

The ink4a/arf tumor suppressors cooperate with p21cip1/waf in the processes of mouse epidermal differentiation, senescence, and carcinogenesis.

In mammalian cells, cell cycle withdrawal is a prerequisite for terminal differentiation. Accordingly, in most tissues, including epidermis, the expression of the cyclin-dependent kinase inhibitors increases during differentiation. However, the actual role of cyclin-dependent kinase inhibitors is unclear. Different aspects of epidermal growth and differentiation in ink4a(Delta2,3)-null, p21-null, and ink4a(Delta2,3)/p21-doubly deficient mice were studied. Altered differentiation and decreased age-related senescence were found in the epidermis of ink4a(Delta2,3)/p21-null mice and, to a lesser extent, in ink4a(Delta2,3)- and p21-null mice. ink4a(Delta2,3)/p21-null primary keratinocytes underwent cell cycle arrest upon calcium or transforming growth factor-beta treatment, but failed to differentiate. This differentiation deficiency was not observed in p21- or ink4a(Delta2,3)-deficient keratinocytes. Upon infection with a v-Ha-ras-coding retrovirus, wild-type keratinocytes displayed features indicative of premature cell senescence. In p21- or ink4a(Delta2,3)-deficient keratinocytes, only a partial response was observed. ink4a(Delta2,3)/p21-deficient keratinocytes did not display senescent features, but showed increased tumorigenic potential upon injection into nude mice. These results indicate that ink4a/arf and cip1/waf genes cooperate to allow normal keratinocyte differentiation and that the absence of both favors malignant transformation.

Animals↗
PubMed2001

Tumor susceptibility of p21(Waf1/Cip1)-deficient mice.

The cell cycle regulator p21 mediates the ability of the tumor suppressor p53 to arrest cellular proliferation. We have examined the involvement of p21 in tumor suppression by following a large cohort of p21-deficient mice for an extended period of time. We report that p21-deficient mice develop spontaneous tumors at an average age of 16 months, whereas wild-type mice are tumor-free beyond 2 years of age. The tumors arising in p21-null mice derive from a variety of cell types and include hematopoietic ( approximately 65% of the tumors), endothelial ( approximately 20%), and epithelial ( approximately 10%) tumors. We have also studied radiation-induced carcinogenesis to test whether, in this setting, p53 exerts its tumor suppressor activity mainly through apoptosis, rather than through p21-mediated cell-cycle arrest. Concurring with this, p21-deficient mice did not show increased susceptibility to radiation-induced carcinogenesis. On the contrary, they were protected relative to wild-type mice. We conclude that p21, by mediating p53-dependent cell-cycle arrest, plays a significant role in tumor suppression.

Animals↗
PubMed2001

Identification of the gene immediately downstream of the murine INK4a/ARF locus.

The tumor suppressor gene ARF is formed by three exons, namely exons 1 beta, 2 and 3. Here, we show that embryo fibroblasts from mice genetically deficient in exons 2 and 3 (Delta 2,3) express a transcript formed by exon 1 beta followed by the 3'-terminal exon of the gene immediately downstream of the INK4a/ARF locus, which we have called NTp16 (Next-To-p16). The chimeric ARF-NTp16 transcript is not detectable in wild-type fibroblasts but its expression level in Delta 2,3 fibroblasts is 30% compared to the level of the normal ARF transcript in wild-type cells. Expression of the ARF-NTp16 transcript in Delta 2,3 cells is subject to normal regulatory features, such as upregulation by the accumulation of cell doublings, and by the presence of oncogenic Ras or E1a. The chimeric ARF-NTp16 transcript has the potential to encode a 17kDa peptide; however, this peptide is not accumulated in cells at detectable levels, probably reflecting poor codon usage or protein instability. We conclude that Delta 2,3 cells do not retain ARF functionality, at least to a significant extent. Interestingly, the expression pattern of the full-length NTp16 gene is altered in several tissues by the presence of the Delta 2,3 mutation. Finally, these data identify the gene immediately downstream of the INK4a/ARF locus, a region that has been previously proposed to contain another tumor suppressor different from the INK4a/ARF genes.

Amino Acid Sequence↗
PubMed2001

Putting the stress on senescence.

Cultivation of primary cells over many generations eventually results in a reproducible loss of proliferative potential that has been termed 'replicative senescence'. Recent work has revealed the heterogeneity of senescence. Importantly, the analysis of the various aspects and types of senescence has turned out to be very informative about numerous in vivo processes, and particularly about carcinogenesis.

Animals↗
PubMed2001

In vitro activities of 10 antifungal drugs against 508 dermatophyte strains.

We have tested 508 strains belonging to 24 species of dermatophytes against 10 antifungal drugs following mainly the NCCLS (M38-P) standard for filamentous fungi. However, several important factors, such as the temperature (28 versus 35 degrees C) and time of incubation (4 to 10 days versus 21 to 74 h), have been modified. The antifungals used were itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, terbinafine, amphotericin B, fluconazole, UR-9825, and G-1. In general, with the exception of fluconazole and G-1, all antifungals were shown to be highly effective.

Antifungal Agents↗
PubMed2001

Forespore-specific transcription of the lonB gene during sporulation in Bacillus subtilis.

The Bacillus subtilis genome encodes two members of the Lon family of prokaryotic ATP-dependent proteases. One, LonA, is produced in response to temperature, osmotic, and oxidative stress and has also been implicated in preventing sigma(G) activity under nonsporulation conditions. The second is encoded by the lonB gene, which resides immediately upstream from lonA. Here we report that transcription of lonB occurs during sporulation under sigma(F) control and thus is restricted to the prespore compartment of sporulating cells. First, expression of a lonB-lacZ transcriptional fusion was abolished in strains unable to produce sigma(F) but remained unaffected upon disruption of the genes encoding the early and late mother cell regulators sigma(E) and sigma(K) or the late forespore regulator sigma(G). Second, the fluorescence of strains harboring a lonB-gfp fusion was confined to the prespore compartment and depended on sigma(F) production. Last, primer extension analysis of the lonB transcript revealed -10 and -35 sequences resembling the consensus sequence recognized by sigma(F)-containing RNA polymerase. We further show that the lonB message accumulated as a single monocistronic transcript during sporulation, synthesis of which required sigma(F) activity. Disruption of the lonB gene did not confer any discernible sporulation phenotype to otherwise wild-type cells, nor did expression of lonB from a multicopy plasmid. In contrast, expression of a fusion of the lonB promoter to the lonA gene severely reduced expression of the sigma(G)-dependent sspE gene and the frequency of sporulation. In confirmation of earlier observations, we found elevated levels of sigma(F)-dependent activity in a spoIIIE47 mutant, in which the lonB region of the chromosome is not translocated into the prespore. Expression of either lonB or the P(lonB)-lonA fusion from a plasmid in the spoIIIE47 mutant reduced sigma(F) -dependent activity to wild-type levels. The results suggest that both LonA and LonB can prevent abnormally high sigma(F) activity but that only LonA can negatively regulate sigma(G).

ATP-Dependent Proteases↗
PubMed2000

Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1.

A senescence-like growth arrest is induced in mouse primary embryo fibroblasts by inhibitors of phosphoinositide 3-kinase (PI3K). We observed that senescence-like growth arrest is correlated with an increase in p27(Kip1) but that down-regulation of other cyclin-dependent kinase (CDK) inhibitors, including p15(INK4b), p16(INK4a), p19( INK4d), and p21(Cip1) as well as other negative cell cycle regulators such as p53 and p19(ARF), implies that this senescence-related growth arrest is independent of the activity of p53, p19(ARF), p16(INK4a), and p21(Cip1), which are associated with replicative senescence. The p27(Kip1) binds to the cyclin/CDK2 complexes and causes a decrease in CDK2 kinase activity. We demonstrated that ectopic expression of p27(Kip1) can induce permanent cell cycle arrest and a senescence-like phenotype in wild-type mouse embryo fibroblasts. We also obtained results suggesting that the kinase inhibitors LY294002 and Wortmannin arrest cell growth and induce a senescence-like phenotype, at least partially, through inhibition of PI3K and protein kinase B/Akt, activation of the forkhead protein AFX, and up-regulation of p27(Kip1)expression. In summary, these observations taken together suggest that p27(Kip1) is an important mediator of the permanent cell cycle arrest induced by PI3K inhibitors. Our data suggest that repression of CDK2 activity by p27(Kip1) is required for the PI3K-induced senescence, yet mouse embryo fibroblasts derived from p27(Kip1-/-) mice entered cell cycle arrest after treatment with LY294002. We show that this is due to a compensatory mechanism by which p130 functionally substitutes for the loss of p27(Kip1). This is the first description that p130 may have a role in inhibiting CDK activity during senescence.

Animals↗
PubMed2000

Tumor suppressors and oncogenes in cellular senescence.

Cyclin-dependent kinase inhibitors p16(INK4a), p21(Cip1), and p27(Kip1) are regarded as key effectors of cellular senescence. In this review, we describe three senescence-inducing pathways involving these inhibitors, namely, the p16(INK4a)/Rb pathway, the p19(ARF)/p53/p21(Cip1) pathway, and the PTEN/p27(Kip1) pathway. We emphasize the participation of tumor suppressors and oncogenes in the regulation of these senescence-inducing pathways. Finally, we discuss the impact of the Ras and Myc oncogenes on the above-mentioned pathways.

Animals↗
PubMed2000

Bacteremic cellulitis caused by Non-01, Non-0139 Vibrio cholerae: report of a case in a patient with hemochromatosis.

We report a case of bacteremia associated with hemorrhagic bullous skin lesions on the leg caused by non-01, non-0139 Vibrio cholerae in a 66-year-old man with hemochromatosis developed in an inland region. The organism was isolated from blood and bullae fluid. The patient was treated successfully with cefotaxime and doxycycline. This report emphasizes the potential of this organism to produce bacteremic cellulitis in people with underlying illness in the absence of usual epidemiological risk factors.

Aged↗
PubMed2000

The cell cycle inhibitor p21 controls T-cell proliferation and sex-linked lupus development.

Here we show that the cell-cycle regulator p21 is involved in immune system function. T lymphocytes from p21-/- mice exhibit significant proliferative advantage over wild-type cells following prolonged stimulation, but not after primary activation. Consistent with this, p21-deficient mice accumulate abnormal amounts of CD4+ memory cells, and develop loss of tolerance towards nuclear antigens. Similar to human lupus, female p21-deficient mice develop antibodies against dsDNA, lymphadenopathy, and glomerulonephritis, leading to decreased viability. These data demonstrate a specialized role for p21 in the control of T-cell proliferation, tolerance to nuclear antigens, and female-prone lupus. These findings could be the basis for new therapeutic approaches to lupus.

Animals↗
PubMed2000

The INK4a/ARF locus in murine tumorigenesis.

The INK4a/ARF locus is regarded as one of the most important anti-tumoral defenses that mammalian organisms possess. The characterization of its two gene products, p16(INK4a) and p19(ARF), has provided a great insight on the functioning of the tumor suppressors Rb and p53, respectively. Present evidence indicates that the INK4a/ARF locus is transcriptionally activated by oncogenic stresses, resulting in cell-cycle arrest or apoptosis. Here, I review the evidence accumulated on the involvement of the INK4a/ARF locus in murine tumorigenesis. Also, I summarize the phenotype of the different transgenic mouse models based on the inactivation of the INK4a/ARF locus.

Alleles↗
PubMed1999

The downregulation of the pro-apoptotic protein Par-4 is critical for Ras-induced survival and tumor progression.

Inhibition of apoptosis is an important characteristic of oncogenic transformation. The Par-4 gene product has recently been shown to be upregulated in cells undergoing apoptotic cell death, and its ectopic expression was shown to be critical in apoptosis. We demonstrate that expression of oncogenic Ras promotes a potent reduction of Par-4 protein and mRNA levels through a MEK-dependent pathway. In addition, the expression of permanently active mutants of MEK, Raf-1 or zetaprotein kinase C but not of phosphatidylinositol 3-kinase (PI 3-kinase) is sufficient to decrease Par-4 levels. These effects are independent of p53, p16 and p19, and were detected not only in fibroblast primary cultures but also in NIH 3T3 and HeLa cells, indicating that they are not secondary to Ras actions on cell cycle regulation. Importantly, restoration of Par-4 levels to normal in Ras-transformed cells makes these cells sensitive to the pro-apoptotic actions of tumor necrosis factor-alpha under conditions in which PI 3-kinase is inhibited and also severely impairs colony formation in soft agar and tumor development in nude mice, as well as increases the sensitivity of these tumors to camptothecin. This indicates that the downregulation of Par-4 by oncogenic Ras is a critical event in tumor progression.

3T3 Cells↗