Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell fate regulation is a function of diverse cell signaling pathways that promote cell survival and or inhibit cell death execution. In this regard, the role of the Bcl-2 family in maintaining a tight balance between cell death and cell proliferation has been extensively studied. The conventional dogma links cell fate regulation by the Bcl-2 family to its effect on mitochondrial permeabilization and apoptosis amplification. However, recent evidence provide a novel mechanism for death regulation by the Bcl-2 family via modulating cellular redox metabolism. For example overexpression of Bcl-2 has been shown to contribute to a pro-oxidant intracellular milieu and down-regulation of cellular superoxide levels enhanced death sensitivity of Bcl-2 overexpressing cells. Interestingly, gene knockdown of the small GTPase Rac1 or pharmacological inhibition of its activity also reverted death phenotype in Bcl-2 expressing cells. This appears to be a function of an interaction between Bcl-2 and Rac1. Similar functional associations have been described between the Bcl-2 family and other members of the Ras superfamily. These interactions at the mitochondria provide novel opportunities for strategic therapeutic targeting of drug-resistant cancers.
 ...
PMID:Crosstalk between Bcl-2 family and Ras family small GTPases: potential cell fate regulation? 2331 76

Mitochondria are the major intracellular source of reactive oxygen species (ROS). While excessive mitochondrial ROS (mitoROS) production induces cell injury and death, there is accumulating evidence that non-toxic low levels of mitoROS could serve as important signaling molecules. Therefore, maintenance of mitoROS at physiological levels is crucial for cell homeostasis as well as for survival and proliferation. This review describes the various mechanisms that keep mitoROS in check, with particular focus on the role of the onco-protein Bcl-2 in redox regulation. In addition to its canonical anti-apoptotic activity, Bcl-2 has been implicated in mitoROS regulation by its effect on mitochondrial complex IV activity, facilitating the mitochondrial incorporation of GSH and interaction with the small GTPase-Rac1 at the mitochondria. We also discuss some of the plausible mechanism(s) which allows Bcl-2 to sense and respond to the fluctuations in mitoROS.
...
PMID:Mitochondrial ROS and involvement of Bcl-2 as a mitochondrial ROS regulator. 2495 15

Mechanical deformation after congenital ureteral obstruction is traduced into biochemical signals leading to tubular atrophy due to epithelial cell apoptosis. We investigated whether Na(+)/H(+) exchanger 1 (NHE1) could be responsible for HK-2 cell apoptosis induction in response to mechanical stretch through its ability to function as a control point of RhoA and MAPK signaling pathways. When mechanical stretch was applied to HK-2 cells, cell apoptosis was associated with diminished NHE1 expression and RhoA activation. The RhoA signaling pathway was confirmed to be upstream from the MAPK cascade when HK-2 cells were transfected with the active RhoA-V14 mutant, showing higher ERK1/2 expression and decreased p38 activation associated with NHE1 downregulation. NHE1 participation in apoptosis induction was confirmed by specific small interfering RNA NHE1 showing caspase-3 activation and decreased Bcl-2 expression. The decreased NHE1 expression was correlated with abnormal NHE1 activity addressed by intracellular pH measurements. These results demonstrate that mitochondrial proximal tubule cell apoptosis in response to mechanical stretch is orchestrated by signaling pathways initiated by the small GTPase RhoA and followed by the opposing effects of ERK1/2 and p38 MAPK phosphorylation, regulating NHE1 decreased expression and activity.
...
PMID:RhoA and MAPK signal transduction pathways regulate NHE1-dependent proximal tubule cell apoptosis after mechanical stretch. 2508 May 24


<< Previous 1 2