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Crosstalk between Bcl-2 family and Ras family small GTPases: potential cell fate regulation?

Kang J, Pervaiz S - Front Oncol (2013)

Bottom Line: The conventional dogma links cell fate regulation by the Bcl-2 family to its effect on mitochondrial permeabilization and apoptosis amplification.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.

View Article: PubMed Central - PubMed

Affiliation: ROS, Apoptosis and Cancer Biology Laboratory, Department of Physiology, Yong Loo Lin School of Medicine Singapore, Singapore ; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore Singapore, Singapore.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Crosstalks between Ras and Bcl-2 family members.
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Figure 1: Crosstalks between Ras and Bcl-2 family members.

Mentions: Bcl-2 family proteins are well-known regulators of apoptosis by virtue of their abilities to either promote (for pro-apoptotic members) or prevent (for anti-apoptotic members) the outer membrane permeabilization through homologous interactions within the family. Recently, an alternative paradigm has surfaced where by overexpression of Bcl-2 confers survival advantage to cancer cells by creating a pro-oxidant milieu. It should be stressed that the Ras superfamily of small GTPases, comprising more than 100 members, is most diverse and versatile in signal transducing capabilities. The founding member Ras and Rac, a member of the Rho subfamily, are implicated in anti-apoptotic signaling, although controversial reports have demonstrated the paradoxical role of both proteins in cell fate decision. The intriguing findings on the associations between Ras GTPases or effectors in the pathway like Raf-1 and Bcl-2 family members, be it direct physical interaction or indirect correlation as summarized in Figure 1, underscores the contrasting effects of Ras family members in promoting cell survival or cell death. In addition, the converging role of Rac1 and Bcl-2 in promoting the pro-oxidant state of cancer cells through physical interaction opens up a new horizon for future redox-based therapeutic designs.


Crosstalk between Bcl-2 family and Ras family small GTPases: potential cell fate regulation?

Kang J, Pervaiz S - Front Oncol (2013)

Crosstalks between Ras and Bcl-2 family members.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539672&req=5

Figure 1: Crosstalks between Ras and Bcl-2 family members.
Mentions: Bcl-2 family proteins are well-known regulators of apoptosis by virtue of their abilities to either promote (for pro-apoptotic members) or prevent (for anti-apoptotic members) the outer membrane permeabilization through homologous interactions within the family. Recently, an alternative paradigm has surfaced where by overexpression of Bcl-2 confers survival advantage to cancer cells by creating a pro-oxidant milieu. It should be stressed that the Ras superfamily of small GTPases, comprising more than 100 members, is most diverse and versatile in signal transducing capabilities. The founding member Ras and Rac, a member of the Rho subfamily, are implicated in anti-apoptotic signaling, although controversial reports have demonstrated the paradoxical role of both proteins in cell fate decision. The intriguing findings on the associations between Ras GTPases or effectors in the pathway like Raf-1 and Bcl-2 family members, be it direct physical interaction or indirect correlation as summarized in Figure 1, underscores the contrasting effects of Ras family members in promoting cell survival or cell death. In addition, the converging role of Rac1 and Bcl-2 in promoting the pro-oxidant state of cancer cells through physical interaction opens up a new horizon for future redox-based therapeutic designs.

Bottom Line: The conventional dogma links cell fate regulation by the Bcl-2 family to its effect on mitochondrial permeabilization and apoptosis amplification.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.

View Article: PubMed Central - PubMed

Affiliation: ROS, Apoptosis and Cancer Biology Laboratory, Department of Physiology, Yong Loo Lin School of Medicine Singapore, Singapore ; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore Singapore, Singapore.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus