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.
Subject(s)
Apoptosis , Peptidylprolyl Isomerase/physiology , Tumor Suppressor Protein p53/metabolism , bcl-2-Associated X Protein/metabolism , Cell Line, Tumor , Humans , Kinetics , NIMA-Interacting Peptidylprolyl Isomerase , Proline/chemistry , Protein Binding , Protein Interaction Domains and Motifs , Stereoisomerism , Tumor Suppressor Protein p53/chemistry , bcl-2-Associated X Protein/chemistryABSTRACT
OBJECTIVE: On magnetic resonance imaging (MRI) for sacroiliitis, increased T2 marrow signal can be misinterpreted as marrow edema. We hypothesize that a changing but predictable pattern for marrow signal intensity adjacent to the sacroiliac joints is present from infancy through skeletal maturity. The purpose of our study is to characterize the distribution of increased T2 signal intensity within the marrow adjacent to the sacroiliac joints in healthy children. SUBJECTS AND METHODS: A retrospective review of the electronic health record identified 345 children who underwent MRI examination of the sacrum, sacroiliac joints, or pelvis. Those with underlying disease that may potentially alter sacroiliac marrow signal were excluded. Sixty children, 30 girls and 30 boys, were assessed for T2 marrow signal intensity greater than the interforaminal sacrum and less than or equivalent to the primary spongiosa of the posterior iliac crests at the S1, S2, and S3 levels. The width of increased T2 signal intensity at each sacral level, right and left sides, ilium, and sacrum was measured (mm). The Mann-Whitney U test was used to determine if there were differences between skeletally immature and skeletally mature subjects; defined as aged 15 years for girls and 17 years for boys. RESULTS: When 30 girls and 30 boys are assessed, the width of increased T2 marrow signal adjacent to the sacroiliac joints is significantly greater in skeletally immature than in skeletal mature female subjects for right S1 sacral side (P = 0.0100), left S1 sacral side (P = 0.0119), right S2 sacral side (P = 0.037), left S2 sacral side (P = 0.0020), and in male subjects for the right S2 sacral side (P = 0.0178), right S2 iliac side (P = 0.0415), right S3 sacral side (P = 0.0024), and left S3 sacral side (P = 0.0037). There were insufficient subjects for whom the ilii extended beyond the S2 sacral segments to assess for the S3 iliac sides. CONCLUSIONS: Healthy children and adolescents have increased T2 signal intensity within the sacral marrow adjacent to the sacroiliac joints, likely the vascular primary spongiosum, which is greater in adolescence compared with skeletal maturity. Knowledge of this normal pattern is beneficial in interpreting MRI examinations for the presence of sacroiliitis.