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Biomedical subjects

Manuel Serrano

Publications and source records attributed to Manuel Serrano.

At least 37 records · Page 2Linked to original sources
PubMed2005

Tumour-suppression activity of the proapoptotic regulator Par4.

The proapoptotic protein encoded by Par4 (prostate apoptosis response 4) has been implicated in tumour suppression, particularly in the prostate. We report here that Par4-null mice are prone to develop tumours, both spontaneously and on carcinogenic treatment. The endometrium and prostate of Par4-null mice were particularly sensitive to the development of proliferative lesions. Most (80%) Par4-null females presented endometrial hyperplasia by 9 months of age, and a significant proportion (36%) developed endometrial adenocarcinomas after 1 year of age. Similarly, Par4-null males showed a high incidence of prostate hyperplasia and prostatic intraepithelial neoplasias, and were extraordinarily sensitive to testosterone-induced prostate hyperplasia. Finally, the uterus and prostate of young Par4-null mice have increased levels of the apoptosis inhibitor XIAP (X-chromosome-linked inhibitor of apoptosis), supporting the previously proposed function of Par4 as an inhibitor of the (zeta)PKC (atypical protein kinase)-NF-(kappa)B (nuclear factor-(kappa)B)-XIAP pathway. These data show that Par4 has an important role in tumour suppression, with a particular relevance in the endometrium and prostate.

Age Factors↗
PubMed2005

Is plasma cardiotrophin-1 a marker of hypertensive heart disease?

OBJECTIVE: This study was designed to investigate whether plasma concentration of cardiotrophin-1 (CT-1), a cytokine that induces cardiomyocyte hypertrophy and stimulates cardiac fibroblasts, is related to hypertensive heart disease, as defined by the presence of echocardiographically assessed left ventricular hypertrophy (LVH). METHODS: The study was performed in 31 normotensive subjects and 111 patients with never-treated essential hypertension (54 without LVH and 57 with LVH). Causes of LVH other than hypertension were excluded after a complete medical workup. A novel enzyme-linked immunosorbent assay was developed to measure plasma CT-1. RESULTS: Plasma CT-1 was increased (P < 0.001) in hypertensives compared with normotensives. The value of CT-1 was higher (P < 0.001) in hypertensives with LVH than in hypertensives without LVH. Some 31% of patients without LVH exhibited values of CT-1 above the upper normal limit in normotensives. A direct correlation was found between CT-1 and left ventricular mass index (r = 0.319, P < 0.001) in all subjects. Receiver operating characteristic curves showed that a cutoff of 39 fmol/ml for CT-1 provided 75% specificity and 70% sensitivity for predicting LVH with a relative risk of 6.21 (95% confidence interval, 2.95 to 13.09). CONCLUSIONS: These results show an association between LVH and the plasma concentration of CT-1 in essential hypertension. Although preliminary, these findings suggest that the determination of CT-1 may be an easy and reliable method for the initial screening and diagnosis of hypertensive heart disease.

Animals↗
PubMed2005

Usefulness of plasma cardiotrophin-1 in assessment of left ventricular hypertrophy regression in hypertensive patients.

OBJECTIVE: We investigated whether regression of left ventricular hypertrophy (LVH) in response to antihypertensive treatment is associated with plasma cardiotrophin-1 (CT-1) in hypertensive patients. METHODS: The study was performed in 47 patients with mild to moderate essential hypertension, and LVH was assessed echocardiographically. The family doctor gave antihypertensive treatment and followed all patients. LVH regression was diagnosed if the baseline left ventricular mass index (LVMI) decreased to normal values after 1 year of treatment. Plasma CT-1 was determined by an enzyme-linked immunosorbent assay. RESULTS: The LVMI was normalized in 23 patients (49%) and persisted at an abnormally increased level in 24 patients (51%) after 1 year of treatment, whereas the reduction in clinic and home blood pressure was similar in the two groups: CT-1 decreased (-48%, P < 0.005) and increased (+35%, P < 0.05) in patients in whom LVH regressed and LVH persisted, respectively. Final values of CT-1 were inversely correlated (r = 0.534, P < 0.001) with the decrease in LVMI after treatment in all patients. A significant association (chi2 = 16.87, P < 0.001) was found between normalization of CT-1 and regression of LVH with treatment. A cut-off value of 41 fmol/ml for CT-1 provided a relative risk of 43.13 (95% confidence interval, 4.88-380.48) for detecting LVH regression. CONCLUSION: These results show an association between treatment-induced decrease of plasma CT-1 and LVH regression in essential hypertension. Although preliminary, these findings suggest that the determination of plasma CT-1 may be useful for the follow-up of hypertensive heart disease in routine clinical practice.

Adult↗
PubMed2005

Growth inhibition by the tumor suppressor p33ING1 in immortalized and primary cells: involvement of two silencing domains and effect of Ras.

ING1 was identified as an inhibitor of growth and has been described as a tumor suppressor. Furthermore, the expression of ING1 is induced in senescent cells and antisense ING1 extends the proliferative life span of primary human fibroblasts. Cooperation of p33ING1 with p53 has been suggested to be an important function of ING1 in cell cycle control. Intriguingly, it has been shown that p33ING1 is associated with histone acetylation as well as with histone deacetylation function. Here we show that p33ING1 is a potent transcriptional silencer in various cell types. However, the silencing function is independent of the presence of p53. By use of deletion mutants two potent autonomous and transferable silencing domains were identified, but no evidence of an activation domain was found. The amino (N)-terminal silencing domain is sensitive to the histone deacetylase inhibitor trichostatin A (TSA) whereas the carboxy-terminal silencing function is resistant to TSA, suggesting that p33ING1 confers gene silencing through both HDAC-dependent and -independent mechanisms. Interestingly, the presence of oncogenic Ras, which is able to induce premature senescence, increases the p33ING1-mediated silencing function. Moreover, ING1-mediated silencing was reduced by coexpressing dominant-negative Ras or by treatment with the mitogen-activated protein kinase inhibitor PD98059 but not by treatment with SB203580, an inhibitor of the p38 pathway. In addition, we show that both silencing domains of ING1 are involved in cell cycle control, as measured by inhibition of colony formation of immortalized cells and by thymidine incorporation of primary human diploid fibroblasts (HDF). Interestingly, p33ING1 expression induces features of cellular senescence in HDFs.

Animals↗
PubMed2004

Crosstalk between PKCzeta and the IL4/Stat6 pathway during T-cell-mediated hepatitis.

PKCzeta is required for nuclear factor kappa-B (NF-kappaB) activation in several cell systems. NF-kappaB is a suppressor of liver apoptosis during development and in concanavalin A (ConA)-induced T-cell-mediated hepatitis. Here we show that PKCzeta-/- mice display inhibited ConA-induced NF-kappaB activation and reduced damage in liver. As the IL-4/Stat6 pathway is necessary for ConA-induced hepatitis, we addressed here the potential role of PKCzeta in this cascade. Interestingly, the loss of PKCzeta severely attenuated serum IL-5 and liver eotaxin-1 levels, two critical mediators of liver damage. Stat6 tyrosine phosphorylation and Jak1 activation were ablated in the liver of ConA-injected PKCzeta-/- mice and in IL-4-stimulated PKCzeta-/- fibroblasts. PKCzeta interacts with and phosphorylates Jak1 and PKCzeta activity is required for Jak1 function. In contrast, Par-4-/- mice have increased sensitivity to ConA-induced liver damage and IL-4 signaling. This unveils a novel and critical involvement of PKCzeta in the IL-4/Stat6 signaling pathway in vitro and in vivo.

Animals↗
PubMed2004

Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging.

Mammalian genes frequently present allelic variants that differ in their expression levels and that, in the case of tumor suppressor genes, can be of relevance for cancer susceptibility and aging. We report here the characterization of a novel mouse model with increased activity for the Ink4a and Arf tumor suppressors. We have generated a "super Ink4a/Arf" mouse strain carrying a transgenic copy of the entire Ink4a/Arf locus. Cells derived from super Ink4a/Arf mice have increased resistance to in vitro immortalization and oncogenic transformation. Importantly, super Ink4a/Arf mice manifest higher resistance to cancer compared to normal, nontransgenic, mice. Finally, super Ink4a/Arf mice have normal aging and lifespan. Together, these results indicate that modest increases in the activity of the Ink4a/Arf tumor suppressor result in a beneficial cancer-resistant phenotype without affecting normal viability or aging.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2004

Different cooperating effect of p21 or p27 deficiency in combination with INK4a/ARF deletion in mice.

The control exerted by the INK4a/ARF locus on cellular proliferation is crucial to restrict tumor development. In agreement with this, mice with defects in this locus are highly tumor prone. However, the potential contribution of other pathways in modulating tumorigenesis in the absence of INK4a/ARF is largely unexplored. In the present study, we investigated the consequences of the combined loss of either of two cyclin-dependent kinase inhibitors, p21 and p27, in cooperation with deletion of the INK4a/ARF locus. Our results show a clear differential effect in tumorigenesis depending on the CKI that is absent. The absence of p21 produced no overt alteration of the lifespan of the INK4a/ARF-null mice, although it modified their tumor spectrum, causing a significant increase in the incidence of fibrosarcomas and the appearance of a small number of rhabdomyosarcomas. In contrast, deficiency of p27 resulted in a significant increase in lethality due to accelerated tumor development, especially in the case of T-cell lymphomas. Finally, combined deficiency of INK4a/ARF and p27 resulted in a significant increase in the number of metastatic tumors. These results demonstrate genetically the oncogenic cooperation between defects on INK4a/ARF and p27, which are common alterations in human cancer.

ADP-Ribosylation Factors↗
PubMed2004

The absence of p53 is critical for the induction of apoptosis by 5-aza-2'-deoxycytidine.

The absence of functional p53 has complex consequences on the cellular responses to cytotoxic drugs. Here, we have examined the role of p53 in the response to 5-aza-2'-deoxycytidine (5-aza-dC or decitabine). Primary mouse embryonic fibroblasts deficient for p53 undergo apoptosis after treatment with 5-aza-dC. When compared with other demethylating drugs or chemotherapeutic treatments, 5-aza-dC showed the highest selectivity ratio for triggering apoptosis in p53-deficient cells relative to wild-type cells. Moreover, the apoptotic efficacy of 5-aza-dC is proprietary of p53-deficient cells, not being observed in cells lacking other cell-cycle regulators, such as p19ARF, p16INK4a, p21(CIP1/WAF1), E2F-1, or E2F-2. Interestingly, treatment with 5-aza-dC results in the same degree of global genomic hypomethylation in wild-type and p53-null cells. However, wild-type cells activate p53 and arrest at G2/M, whereas p53-null cells accumulate severe chromosomal aberrations and undergo apoptosis. Significantly, the impact of p53-deficiency on the response to 5-aza-dC is not exclusive of primary non-neoplastic cells, but it is also present in neoplastically transformed cells. Finally, treatment of mice bearing genetically defined tumors with nontoxic doses of 5-aza-dC results in therapeutical responses only on tumors lacking p53, but not on tumors lacking p19ARF. Together, our results put forward the hypothesis that the absence of p53 may determine a higher chemotherapeutic index for 5-aza-dC.

Animals↗
PubMed2004

The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis.

The atypical PKCs (aPKCs) have been implicated genetically in at least two independent signaling cascades that control NF-kappa B and cell polarity, through the interaction with the adapters p62 and Par-6, respectively. P62 binds TRAF6, which plays an essential role in osteoclastogenesis and bone remodeling. Recently, p62 mutations have been shown to be the cause of the 5q35-linked Paget's disease of bone, a genetic disorder characterized by aberrant osteoclastic activity. Here we show that p62, like TRAF6, is upregulated during RANK-L-induced osteoclastogenesis and that the genetic inactivation of p62 in mice leads to impaired osteoclastogenesis in vitro and in vivo, as well as inhibition of IKK activation and NF-kappa B nuclear translocation. In addition, RANK-L stimulation leads to the inducible formation of a ternary complex involving TRAF6, p62, and the aPKCs. These observations demonstrate that p62 is an important mediator during osteoclastogenesis and induced bone remodeling.

Animals↗
PubMed2003

Regulation of mature T lymphocyte proliferation and differentiation by Par-4.

The genetic inactivation of the atypical protein kinase C (aPKC) inhibitor, Par-4, gives rise to increased NF-kappaB activation and decreased stimulation of JNK in embryo fibroblasts. Here we have characterized the immunological phenotype of the Par-4(-/-) mice and found that the loss of this gene leads to an increased proliferative response of peripheral T cells when challenged through the TCR. This is accompanied by a higher increase in cell cycle entry and inhibition of apoptosis, with enhanced IL-2 secretion but normal CD25 synthesis. Interestingly, the TCR-triggered activation of NF-kappaB was augmented and that of JNK was severely abrogated. Consistent with previous data from knock outs of different JNKs, NFATc1 activation and IL-4 secretion were augmented in the Par-4-deficient CD4+ T cells, suggesting that the loss of Par-4 drives T-cell differentiation towards a Th2 response. This is compelling evidence that Par-4 is a novel modulator of the immune response through its ability to impact aPKC activity, which translates into lower JNK signaling.

Animals↗
PubMed2003

[Smoking cessation and risk of myocardial reinfarction in coronary patients: a nested case-control study].

INTRODUCTION AND OBJECTIVES: Smoking cessation reduces mortality in coronary patients. The aim of this study was to estimate association measures between the risk of occurrence of fatal or non-fatal reinfarction in patients who either continue to smoke or stop after a first infarction and are treated with secondary prevention measures. PATIENTS AND METHOD: The study was a case-control (1:1) design nested in a cohort of 985 coronary patients under the age of 76 years who were not treated with invasive procedures and survived more than 6 months after the first acute myocardial infarction. Cases were all patients who suffered reinfarction (n = 137) between 1997 and 2000. A control patient was matched with each case by gender, age, hospital, interviewer, and the secondary prevention timeframe. RESULTS: Patients who smoke after the first acute myocardial infarction had an Odds ratio (OR) of 2.83 (95% CI, 1.47-5.47) for a new acute myocardial infarction. Adjustment for lifestyle, drug treatment, and risk factors (family history of coronary disease, high blood pressure, hypercholesterolemia, and diabetes mellitus) did not change the OR (2.80 [95% CI, 1.35-5.80]). Patients who quit smoking had an adjusted OR of 0.90 (95% CI, 0.47-1.71) compared with non-smokers before the first acute myocardial infarction. Continued smoking had an adjusted OR of 2.90 (95% CI, 1.35-6.20) compared to quitting after the first acute myocardial infarction. CONCLUSION: The risk of acute myocardial infarctions is three times higher in patients who continue to smoke after an acute coronary event compared with patients who quit. The risk of reinfarction in patients who stop smoking is similar to the risk of non-smokers before the first infarction.

Aged↗
PubMed2003

Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context.

We have targeted a K-ras allele in mouse embryonic stem (ES) cells to express a K-Ras(V12) oncoprotein along with a marker protein (beta-geo) from a single bicistronic transcript. Expression of this oncogenic allele requires removal of a knocked in STOP transcriptional cassette by Cre recombinase. Primary mouse embryonic fibroblasts expressing this K-ras(V12) allele do not undergo proliferative senescence and proliferate as immortal cells. In mice, expression of K-ras(V12) throughout the body fails to induce unscheduled proliferation or other growth abnormalities for up to eight months. Only a percentage of K-ras(V12)-expressing lung bronchiolo-alveolar cells undergo malignant transformation leading to the formation of multiple adenomas and adenocarcinomas. These results indicate that neoplastic growth induced by an endogenous K-ras oncogene depends upon cellular context.

Animals↗
PubMed2003

Genetic inactivation of Par4 results in hyperactivation of NF-kappaB and impairment of JNK and p38.

The Par4 gene was first identified in prostate cells undergoing apoptosis after androgen withdrawal. PAR4 was subsequently shown to interact with, and inhibit, atypical protein kinase C isoforms, functioning as a negative regulator of the NF-kappaB pathway. This may explain its pro-apoptotic function in overexpression experiments. To determine the physiological role of PAR4, we have derived primary embryonic fibroblasts (EFs) from Par4(-/-) mice. We show here that loss of PAR4 leads to a reduction in the ability of tumour necrosis factor-alpha (TNF-alpha) to induce apoptosis by increased activation of NF-kappaB. Consistent with recent reports demonstrating the antagonistic actions of NF-kappaB and c-Jun amino-terminal kinase (JNK) signalling, we have found that Par4(-/-) cells show a reduced activation of the sustained phase of JNK and p38 stimulation by TNF-alpha and interleukin 1. Higher levels of an anti-apoptotic JNK-inhibitor protein, X-chromosome-linked inhibitor of apoptosis, in Par4(-/-) EFs might explain the inhibition of JNK activation in these cells.

Animals↗
PubMed2003

Engineering cancer resistance in mice.

Research on cancer has benefited enormously from the genetic manipulation of mice. Until recently, most of the emphasis has been put on tailoring genetic alterations to accelerate tumorigenesis or to recapitulate particular aspects of the tumorigenic process. The goal of engineering mice with an increased resistance to cancer is a novel aspect that is of importance to understand cancer susceptibility and to validate therapeutic and chemopreventive strategies. Here, we review the different mouse models described to date that manifest a 'cancer resistance' phenotype, with a particular emphasis on the molecular basis of the resistance and on the associated phenotypes that may have a negative impact on health.

Animals↗
PubMed2002

Activation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1).

Deregulation of D-type cyclin-dependent kinases (CDK4 and 6) is widely observed in various human cancers, illustrating their importance in cell cycle control. Like other cyclin-dependent kinases (CDKs), assembly with cyclins is the most critical step for activation of CDK4/6. As previously reported elsewhere, we observed that the level of cyclinD1-CDK4 complex and its associated kinase activity were significantly low in asynchronously proliferating mouse embryo fibroblasts lacking both p21(Cip1) and p27(Kip1) (p21/p27-null MEFs). These evidences imply that p21(Cip1) and p27(Kip1) CDK inhibitors are 'essential activators' of cyclin D-kinases. We, however, discovered here that both the assembly and activation of cyclin D1-CDK4 complex occur when quiescent p21/p27-null MEFs were stimulated to re-enter the cell cycle. This mitogen-induced cyclin D1-kinase activity was blocked by overexpression of p16(INK4a) and resulted in the inhibition of S phase entry in p21/p27-null MEFs. Furthermore, ectopic expression of p34(SEI-1), a mitogen-induced CDK4 binding protein, increased the levels of active cyclinD1-CDK4 complex in asynchronously proliferating p21/p27-null MEFs. Together, our results suggest that there are several independent ways to stimulate the assembly of cyclin D1-CDK4 kinases. Although p21(Cip1) and p27(Kip1) play a role in this process, our results demonstrate that additional mechanisms must occur in G0 to S phase transition.

Animals↗
PubMed2002

"Super p53" mice exhibit enhanced DNA damage response, are tumor resistant and age normally.

The tumor suppressor p53 is critical in preventing cancer due to its ability to trigger proliferation arrest and cell death upon the occurrence of a variety of stresses, most notably, DNA damage and oncogenic stress. Here, we report the generation and characterization of mice carrying supernumerary copies of the p53 gene in the form of large genomic transgenes. Prior to this, we demonstrate that the p53 transgenic allele (p53-tg), when present in a p53-null genetic background, behaves as a functional replica of the endogenous gene. "Super p53" mice, carrying p53-tg alleles in addition to the two endogenous alleles, exhibit an enhanced response to DNA damage. Importantly, "super p53" mice are significantly protected from cancer when compared with normal mice. Finally, in contrast to previously reported mice with constitutively active p53, "super p53" mice do not show any indication of premature aging, probably reflecting the fact that p53 is under normal regulatory control. Together, our results prove that cancer resistance can be enhanced by a simple genetic modification and in the absence of undesirable effects.

Aging↗
PubMed2002

Activation of ARF by oncogenic stress in mouse fibroblasts is independent of E2F1 and E2F2.

The ARF tumour suppressor protein (p14(ARF) in human and p19(ARF) in mouse) is a major mediator of the activation of p53 in response to oncogenic stress. Little is known about the signalling pathways connecting oncogenic stimuli to the activation of ARF. Regulation of ARF occurs primarily at the transcriptional level and several modulators of ARF transcription have been identified. Notably, ectopic expression of E2F1 upregulates ARF transcriptionally, and both E2F1 and ARF have been implicated in apoptosis and cell-cycle arrest. We have used primary mouse fibroblasts deficient for E2F1, E2F2, or both to determine the possible role of these E2F proteins as upstream regulators of ARF in response to oncogenic stimuli and other stresses. In particular, we have studied the effects of oncogenic Ras and the viral oncoprotein E1A on ARF levels, neoplastic transformation, and sensitization to apoptosis. We have also examined the behaviour of the E2F-deficient MEFs with respect to immortalization and sensitivity to DNA damage. None of the ARF-mediated responses that we have analysed is significantly affected in E2F1(-/-), E2F2(-/-) or E2F1/2(-/-) MEFs, and ARF is upregulated normally in all cases. Taken together, our results indicate that the activation of ARF in response to oncogenic stress can occur by E2F1- and E2F2-independent mechanisms. This challenges previous suggestions implicating E2F factors as key mediators in the activation of ARF by oncogenic stress.

Adenovirus E1A Proteins↗