Biophysics. Harvesting energy by improving the economy of human walking.

alternative explanations are necessary to accommodate all the available data. A number of studies have shown that p53 moves to the mitochondria in response to stress, suggesting that translocation and binding of p53 to mitochondrial Bcl2 and Bcl-xL may also trigger apoptosis (10). In this model the mitochondrial p53 could function as an enabler BH3-only protein to release activa-tors like Bid (see the figure, top). Mitochondrial p53 can also show activator functions such as binding to Bak, which results in the release of Bak from Mcl1 (an anti-apoptotic protein similar to Bcl2 and Bcl-xL) (11). Direct activation of Bax by p53 appears to take place in the cytosol (9). To address the relative importance of enabler and activator functions of p53, Chipuk et al. used a Bcl-xL mutant that binds p53 but not PUMA. Although both wild-type and mutant Bcl-xL inhibited p53-mediated apoptosis, expression of PUMA could only reverse the effect of wild-type Bcl-xL. The implication is therefore that p53 has to be released from Bcl-xL by PUMA to induce apoptosis and that the binding of p53 to Bcl-xL is by itself not a proapoptotic signal. While providing elegant support for the activator function of p53, this observation does not preclude a function for p53 as an enabler and overall it seems likely that coordination of the nuclear, cytoplasmic, and mitochondrial functions of p53 will contribute to the ultimate response to stress. A number of questions arise out of the Chipuk et al. study, including whether p53 requires PUMA, or PUMA requires p53, to induce cell death. The answer to the first question, at least in some cell types, seems to be yes. Deletion of PUMA by genetic knockout or knockdown by RNA interference strategies strongly impairs p53-dependent apoptosis in certain cell systems (3). But PUMA may not be unique in this function. A number of other BH3-only proteins , such as Noxa, are transcriptionally activated by p53 and play an essential role in the p53 apoptotic response in some cell types. So it seems likely that under certain conditions, proteins like Noxa might substitute for PUMA. Less clear is whether PUMA might require p53. Initial studies have indicated that PUMA expression is enhanced by withdrawal of serum from cells or by inducing stress in the endoplasmic reticulum, and that this induction of PUMA is p53 independent (12, 13). Furthermore, like p53, the transcription factor E2F1 can activate PUMA expression, …