Editors' ChoiceCell Biology

Mitochondrial Rb Promotes Apoptosis

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Sci. Signal.  28 May 2013:
Vol. 6, Issue 277, pp. ec118
DOI: 10.1126/scisignal.2004367

The tumor suppressor retinoblastoma (Rb) is a transcriptional coregulator that inhibits cell cycle progression and promotes expression of proapoptotic genes. Hilgendorf et al. found that Rb also functions at mitochondria to promote apoptosis. Using immortalized rat fibroblasts and primary human IMR90 fibroblasts, the authors demonstrated that overexpression of Rb enhanced cell death in response to tumor necrosis factor–α (TNF-α), even in the presence of the protein translation inhibitor cycloheximide, and that knocking down endogenous Rb reduced TNF-α–induced cell death. The ability of Rb to mediate cell death in mouse embryonic fibroblasts required the proapoptotic protein Bax, which promotes permeabilization of the outer mitochrondrial membrane. Like Bax, Rb was present in the outer mitochondrial membrane fraction of lysates from mouse livers. Experiments in cultured cells and with liposomes were consistent with Rb promoting the membrane permeabilization activity of Bax. Bax and Rb coimmunoprecipitated from IMR90 cell lysates, and in vitro binding assays indicated that Rb interacted directly with Bax and promoted its conversion into its active conformation. Transgenic expression of an engineered form of Rb that localized exclusively to mitochondria inhibited the growth of Rb–/–;p53–/– osteosarcoma xenografts in mice. This nontranscriptional role for Rb is similar to that of p53, which is a transcription factor that also promotes apoptosis through a nontranscriptional mechanism at mitochondria. In related commentary, Attardi and Sage consider these findings in the context of the history of Rb research.

K. I. Hilgendorf, E. S. Leshchiner, S. Nedelcu, M. A. Maynard, E. Calo, A. Ianari, L. D. Walensky, J. A. Lees, The retinoblastoma protein induces apoptosis directly at the mitochondria. Genes Dev. 27, 1003–1015 (2013). [Abstract] [Full Text]

L. D. Attardi, J. Sage, RB goes mitochondrial. Genes Dev. 27, 975–979 (2013). [Abstract] [Full Text]