Pin1-Induced Proline Isomerization in Cytosolic p53 Mediates BAX Activation and Apoptosis

Ariele Viacava Follis; Fabien Llambi; Parker Merritt; Jerry E. Chipuk; Douglas R. Green; Richard W. Kriwacki

doi:10.1016/j.molcel.2015.06.029

Pin1-Induced Proline Isomerization in Cytosolic p53 Mediates BAX Activation and Apoptosis

Ariele Viacava Follis, Fabien Llambi, Parker Merritt, Jerry E. Chipuk, Douglas R. Green, Richard W. Kriwacki

Research output: Contribution to journal › Article › peer-review

91 Scopus citations

Abstract

The cytosolic fraction of the tumor suppressor p53 activates the apoptotic effector protein BAX to trigger apoptosis. Here we report that p53 activates BAX through a mechanism different from that associated with activation by BH3 only proteins (BIM and BID). We observed that cis-trans isomerization of proline 47 (Pro₄₇) within p53, an inherently rare molecular event, was required for BAX activation. The prolyl isomerase Pin1 enhanced p53-dependent BAX activation by catalyzing cis-trans interconversion of p53 Pro₄₇. Our results reveal a signaling mechanism whereby proline cis-trans isomerization in one protein triggers conformational and functional changes in a downstream signaling partner. Activation of BAX through the concerted action of cytosolic p53 and Pin1 may integrate cell stress signals to induce a direct apoptotic response.

Original language	English
Pages (from-to)	677-684
Number of pages	8
Journal	Molecular Cell
Volume	59
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2015.06.029
State	Published - 20 Aug 2015

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title = "Pin1-Induced Proline Isomerization in Cytosolic p53 Mediates BAX Activation and Apoptosis",

abstract = "The cytosolic fraction of the tumor suppressor p53 activates the apoptotic effector protein BAX to trigger apoptosis. Here we report that p53 activates BAX through a mechanism different from that associated with activation by BH3 only proteins (BIM and BID). We observed that cis-trans isomerization of proline 47 (Pro47) within p53, an inherently rare molecular event, was required for BAX activation. The prolyl isomerase Pin1 enhanced p53-dependent BAX activation by catalyzing cis-trans interconversion of p53 Pro47. Our results reveal a signaling mechanism whereby proline cis-trans isomerization in one protein triggers conformational and functional changes in a downstream signaling partner. Activation of BAX through the concerted action of cytosolic p53 and Pin1 may integrate cell stress signals to induce a direct apoptotic response.",

author = "Follis, {Ariele Viacava} and Fabien Llambi and Parker Merritt and Chipuk, {Jerry E.} and Green, {Douglas R.} and Kriwacki, {Richard W.}",

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doi = "10.1016/j.molcel.2015.06.029",

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T1 - Pin1-Induced Proline Isomerization in Cytosolic p53 Mediates BAX Activation and Apoptosis

AU - Follis, Ariele Viacava

AU - Llambi, Fabien

AU - Merritt, Parker

AU - Chipuk, Jerry E.

AU - Green, Douglas R.

AU - Kriwacki, Richard W.

PY - 2015/8/20

Y1 - 2015/8/20

N2 - The cytosolic fraction of the tumor suppressor p53 activates the apoptotic effector protein BAX to trigger apoptosis. Here we report that p53 activates BAX through a mechanism different from that associated with activation by BH3 only proteins (BIM and BID). We observed that cis-trans isomerization of proline 47 (Pro47) within p53, an inherently rare molecular event, was required for BAX activation. The prolyl isomerase Pin1 enhanced p53-dependent BAX activation by catalyzing cis-trans interconversion of p53 Pro47. Our results reveal a signaling mechanism whereby proline cis-trans isomerization in one protein triggers conformational and functional changes in a downstream signaling partner. Activation of BAX through the concerted action of cytosolic p53 and Pin1 may integrate cell stress signals to induce a direct apoptotic response.

AB - The cytosolic fraction of the tumor suppressor p53 activates the apoptotic effector protein BAX to trigger apoptosis. Here we report that p53 activates BAX through a mechanism different from that associated with activation by BH3 only proteins (BIM and BID). We observed that cis-trans isomerization of proline 47 (Pro47) within p53, an inherently rare molecular event, was required for BAX activation. The prolyl isomerase Pin1 enhanced p53-dependent BAX activation by catalyzing cis-trans interconversion of p53 Pro47. Our results reveal a signaling mechanism whereby proline cis-trans isomerization in one protein triggers conformational and functional changes in a downstream signaling partner. Activation of BAX through the concerted action of cytosolic p53 and Pin1 may integrate cell stress signals to induce a direct apoptotic response.

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JO - Molecular Cell

JF - Molecular Cell

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Pin1-Induced Proline Isomerization in Cytosolic p53 Mediates BAX Activation and Apoptosis

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