Abstract
BackgroundThe retinoblastoma protein (Rb) plays a central role in the regulation of cell cycle, differentiation and apoptosis. In cancer cells, ablation of Rb function or its pathway is a consequence of genetic inactivation, viral oncoprotein binding or deregulated hyperphosphorylation. Some recent data suggest that Rb relocation could also account for the regulation of its tumor suppressor activity, as is the case for other tumor suppressor proteins, such as p53.ResultsIn this reported study, we present evidence that a fraction of the total amount of Rb protein can localize to the mitochondria in proliferative cells taken from both rodent and human cells. This result is also supported by the use of Rb siRNAs, which substantially reduced the amount of mitochondrial Rb, and by acellular assays, in which [35S]-Methionine-labeled Rb proteins bind strongly to mitochondria isolated from rat liver. Moreover, endogenous Rb is found in an internal compartment of the mitochondria, within the inner-membrane. This is consistent with the protection of Rb from alkaline treatment, which destroys any interaction of proteins that are weakly bound to mitochondria.ConclusionAlthough a few data regarding an unspecific cytosolic localization of Rb protein have been reported for some tumor cells, our results are the first evidence of a mitochondrial localization of Rb. The mitochondrial localization of Rb is observed in parallel with its classic nuclear location and paves the way for the study of potential as-yet-unknown roles of Rb at this site.
Highlights
The retinoblastoma protein (Rb) plays a central role in the regulation of cell cycle, differentiation and apoptosis
Putative contamination of the mitochondrial fractions was monitored by detecting cytosolic and nuclear (PCNA or lamin A) marker proteins, and antibodies directed against COX cytochrome c oxydase II complex (II) or cytochrome c confirmed the enrichment of mitochondrial fractions
As already outlined, the Rb protein is detected in nuclear fractions of untreated human cells, yet, surprisingly, a fraction of Rb is detected in the mitochondrial fractions of these cells (Fig. 1A, lane 3 and 5), suggesting that Rb may be located at this site in parallel with the classically-described nuclear localization
Summary
The retinoblastoma protein (Rb) plays a central role in the regulation of cell cycle, differentiation and apoptosis. Ablation of Rb function or its pathway is a consequence of genetic inactivation, viral oncoprotein binding or deregulated hyperphosphorylation. Its loss of function is linked to the development of numerous human cancers [2]. This protein is a major regulator of cell cycle, differentiation and apoptosis. Some reports demonstrate that Rb can act as an inducer of cell death and point to a controversial role for this protein in the regulation of apoptosis [6]
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