Nuevo mecanismo de regulacion postraduccional

[Protein Synthesis, Post-Translational Modification, and Degradation] Adenosine Receptors Control a New Pathway of Fas-associated Death Domain Protein Expression Regulation by Secretion
from Journal of Biological Chemistry current issue by Tourneur, L., Mistou, S., Schmitt, A., Chiocchia, G.

FADD is the key adaptor transmitting the apoptotic signal mediated by death receptors. We have previously shown that FADD protein expression could be lost in vivo in cancerous cells, in mice and humans, and be used as prognostic factor. Furthermore, loss of FADD could contribute to tumor progression and aggressiveness. However, the mechanism accounting for the loss of FADD was unknown. Using in vitro-cultured mouse organ models, we demonstrated that loss of FADD occurred through a new regulatory pathway of FADD expression by secretion. The secretion of FADD is an active release following shedding of microvesicles derived from the plasma membrane. In our experimental settings, this phenomenon was restricted to 6 of 12 FADD-expressing organs. This process is calcium- and adenosine-dependent. Moreover, we identified the two receptors with low affinity to adenosine, namely A2B and A3 adenosine receptors, as regulators of the FADD secretion process. Furthermore, we showed that modulating A3 adenosine receptor can convert a nonsecreting organ into a FADD-secreting one. Finally, we reported that mouse FADD release occurred in vivo during tumor disease. These results demonstrate the existence of a new localization site (in microvesicles) and regulatory mechanism (by secretion) of the FADD protein, and the implication of adenosine receptors in this process. These data open a new field of investigation consisting of the possibility to regulate FADD expression via the modulation of adenosine receptors, which constitutes a therapeutic target in diseases in which FADD-mediated signaling is impaired.

SATB1 paper importante

Nature Clinical Practice Oncology (2008) 5, 364
doi:10.1038/ncponc1141

SATB1 expression generates gene-expression profiles that promote breast tumor metastasis

Original article

Han HJ et al. (2008) SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis. Nature 452: 187–193 PubMed

Gene-expression analyses of human breast cancer cell lines that are associated with a poor outcome have revealed characteristic expression patterns that can predict metastasis (or metastatic risk), but how such gene-expression profiles confer metastatic potential is unclear. Han et al. have described a genome organizer protein—SATB1—that when expressed in breast cancer cells can establish a pattern of gene expression that is consistent with invasive behavior.

Initial investigations involving breast epithelial cell lines and breast-tumor specimens revealed that SATB1 is expressed only in metastatic cancer cell lines. To determine the prognostic significance of SATB1 expression, tissue microarrays comprising 1,318 breast cancer samples were scored on the basis of expression levels of SATB1 protein in tumor cell nuclei. Kaplan–Meier analysis of data from 985 patients with ductal breast carcinomas revealed a correlation between higher levels of SATB1 expression and shorter overall patient survival (P <0.001).>in vitro proliferation, restored anchorage-dependent growth and breast-like acinar polarity, and inhibited tumor growth and metastasis in vivo. Consistent with these findings, ectopic expression of SATB1 in a nonmetastatic cell line was sufficient to confer invasive activity in vivo. Global gene-expression profiling showed that expression of SATB1 altered the expression patterns of over 1,000 genes. Further analysis revealed that SATB1 modified the epigenetic status of all SATB1-dependent genes analyzed.

The authors conclude that SATB1 establishes gene-expression profiles that promote tumor growth and metastasis.

La caspasa 9 debe procesarse en la apoptosis?

COMMENTARY
Caspase-9 cleavage, do you need it?
Davina TWIDDY and Kelvin CAIN1
MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Rd, Leicester LE1 9HN, U.K.
Caspase-9, which is activated by association with the Apaf-1
(apoptotic protease-activating factor-1) apoptosome complex,
cleaves and activates the downstream effector caspases-3 and -7,
thereby executing the caspase-cascade and cell-death programme.
Although caspase-9 does not need to be cleaved to be active, apoptotic
cell death is always accompanied by autocatalytic cleavage
and by further downstream effector caspase-dependent cleavage
of caspase-9. In this issue of the Biochemical Journal,Denault
and co-workers evaluate the role of caspase-3-dependent cleavage
of caspase-9 and conclude that this mechanism mainly serves
to enhance apoptosis by alleviating XIAP (X-linked inhibitor of
apoptosis) inhibition of the apical caspase.
Biochem. J. (2007) 405, e1–e2 (Printed in Great Britain) doi:10.1042/BJ20070617

Promotores y splicing

Alternative Promoters Influence Alternative Splicing at the Genomic Level

Abstract

Background

More and more experiments have shown that transcription and mRNA processing are not two independent events but are tightly coupled to each other. Both promoter and transcription rate were found to influence alternative splicing. More than half of human genes have alternative promoters, but it is still not clear why there are so many alternative promoters and what their biological roles are.

Methodology/Principal Findings

In this study, we explored whether there is a functional correlation between alternative promoters and alternative splicing by a genome-wide analysis of human and mouse genes. We constructed a large data set of genes with alternative promoter and alternative splicing annotations. By analyzing these genes, we showed that genes with alternative promoters tended to demonstrate alternative splicing compare to genes with single promoter, and, genes with more alternative promoters tend to have more alternative splicing variants. Furthermore, transcripts from different alternative promoters tended to splice differently.

Conclusions/Significance

Thus at the genomic level, alternative promoters are positively correlated with alternative splicing.

ver articulo en PLOS one

Salud en Mexico. PLOS Medicine

Characterizing the Epidemiological Transition in Mexico: National and Subnational Burden of Diseases, Injuries, and Risk Factors

Gretchen Stevens^1,2,3*, Rodrigo H. Dias², Kevin J. A. Thomas⁴, Juan A. Rivera⁵, Natalie Carvalho², Simón Barquera⁵, Kenneth Hill², Majid Ezzati^1,2

1 Harvard School of Public Health, Boston, Massachusetts, United States of America, 2 Harvard Initiative for Global Health, Cambridge, Massachusetts, United States of America, 3 World Health Organization, Geneva, Switzerland, 4 Pennsylvania State University, University Park, Pennsylvania, United States of America, 5 Instituto Nacional de Salud Pública, Cuernavaca, Mexico

Background

Rates of diseases and injuries and the effects of their risk factors can have substantial subnational heterogeneity, especially in middle-income countries like Mexico. Subnational analysis of the burden of diseases, injuries, and risk factors can improve characterization of the epidemiological transition and identify policy priorities.

Methods and Findings

We estimated deaths and loss of healthy life years (measured in disability-adjusted life years [DALYs]) in 2004 from a comprehensive list of diseases and injuries, and 16 major risk factors, by sex and age for Mexico and its states. Data sources included the vital statistics, national censuses, health examination surveys, and published epidemiological studies. Mortality statistics were adjusted for underreporting, misreporting of age at death, and for misclassification and incomparability of cause-of-death assignment. Nationally, noncommunicable diseases caused 75% of total deaths and 68% of total DALYs, with another 14% of deaths and 18% of DALYs caused by undernutrition and communicable, maternal, and perinatal diseases. The leading causes of death were ischemic heart disease, diabetes mellitus, cerebrovascular disease, liver cirrhosis, and road traffic injuries. High body mass index, high blood glucose, and alcohol use were the leading risk factors for disease burden, causing 5.1%, 5.0%, and 7.3% of total burden of disease, respectively. Mexico City had the lowest mortality rates (4.2 per 1,000) and the Southern region the highest (5.0 per 1,000); under-five mortality in the Southern region was nearly twice that of Mexico City. In the Southern region undernutrition and communicable, maternal, and perinatal diseases caused 23% of DALYs; in Chiapas, they caused 29% of DALYs. At the same time, the absolute rates of noncommunicable disease and injury burdens were highest in the Southern region (105 DALYs per 1,000 population versus 97 nationally for noncommunicable diseases; 22 versus 19 for injuries).

Conclusions

Mexico is at an advanced stage in the epidemiologic transition, with the majority of the disease and injury burden from noncommunicable diseases. A unique characteristic of the epidemiological transition in Mexico is that overweight and obesity, high blood glucose, and alcohol use are responsible for larger burden of disease than other noncommunicable disease risks such as tobacco smoking. The Southern region is least advanced in the epidemiological transition and suffers from the largest burden of ill health in all disease and injury groups.

Creacion de nuevos genes

Research Highlight

Nature Reviews Genetics 9, 415 (June 2008) | doi:10.1038/nrg2394

Evolution: A gene is born

Tanita Casci

There are various ways to explain how new genes can come about — exon shuffling, gene duplication and retroposition being just a few. But how are truly novel genes born out of a sequence that was previously non-coding? Using a comparative genomics approach, a research group has identified and characterized the function of a novel ORF in Saccharomyces cerevisiae, and has shown that it might contribute to the evolution of this yeast species.

The mechanism by which a gene is created from scratch receives relatively little attention, despite reports from sequencing projects and comparative analyses that many de novo genes exist in some bacterial and animal lineages. To investigate the process of gene creation, the authors concentrated on BSC4, a species-specific gene that was pulled out of genome comparisons among Saccharomyces species. Although the gene has no homologue in other fungal species, the region around BSC4 is syntenic across Saccharomyces species — suggesting that it probably did not jump into its current position on the S. cerevisiae genome by horizontal gene transfer, and allowing the birth of the BSC4 ancestral sequence to be dated to over 100 million years ago.

How do we know that BSC4 is a real protein-coding gene? Most criteria would suggest that it is: the sequence — an ORF of 132 amino acids — is fixed in S. cerevisiae strains, and RT-PCR experiments suggest that the ORF can be transcribed. Proteomics analyses support the existence of 29 peptides associated with this locus, and the BCS4 sequence seems to be under purifying selection. It is not clear what BSC4 actually does, but the fact that it is synthetically lethal with mutations in two DNA-damage repair genes makes it likely that it acts in this pathway.

This paper provides the first evidence that new genes can arise from a non-coding region that is initially transcribed and then subsequently obtains an ORF via mutation. The fact that BSC4 expression is upregulated during the stationary phase of the cell cycle, when DNA repair is most pressing, supports the idea that not only is this new gene real, it is also selectively advantageous.