Linked Life Data

17320350

Source:http://linkedlifedata.com/resource/pubmed/id/17320350

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2007-4-20
pubmed:abstractText
Smac/DIABLO is a mitochondrial protein that participates in apoptotic cell death by means of sequestering several members of the inhibitor of apoptosis protein family. This action allows caspase activation, cleavage of key cellular substrates and death. Release from mitochondria is considered the main regulatory step of Smac/DIABLO activity. Nevertheless, the fact that at least one isoform, Smac-beta, does not reside in this organelle implies that transcriptional regulation could also be important. cAMP is a well known second messenger with important apoptotic effects. To analyze if cAMP could be involved in Smac/DIABLO gene regulation, we analyzed 2903 base pairs upstream of the coding sequence and characterized the minimal promoter, which contains a consensus CRE site. We found that cAMP/PKA/CREB pathway is indeed an important regulator of Smac/DIABLO transcription, since exposure to the cAMP analog 8-CPT-cAMP, the adenylyl cyclase activator forskolin, the inhibitor of phosphodiesterase isobutylmethylxanthine or by hindering PKA activation with H89, regulated the promoter activity, as shown by gene reporter and RT-PCR assays. Additionally, the results of site-directed mutagenesis revealed that the consensus CRE site was biologically functional and required for cAMP-induced promoter activity in human HeLa cells. Supporting these results, a negative dominant version of the protein kinase A responsive factor, KCREB, reduced basal Smac/DIABLO expression and rendered the promoter unresponsive to cAMP. Reducing Smac expression using an antisense approach blocked the apoptosis effects of cAMP in cervical cancer cells. These results show that cAMP is an important modulator of the apoptotic threshold in cancer cell by means of regulating Smac/DIABLO expression.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0898-6568
pubmed:author
pubmed:issnType
Print
pubmed:volume
19
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1212-20
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Apoptosis induced by cAMP requires Smac/DIABLO transcriptional upregulation.
pubmed:affiliation
Molecular Biology Laboratory, Subdireccion de Investigacion Basica, Instituto Nacional de Cancerologia, Mexico City, Mexico.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't