Cyclin B1/Cdk1 phosphorylation of mitochondrial p53 induces anti-apoptotic response.

The pro-apoptotic function of p53 has been well defined in preventing genomic instability and cell transformation. However, the intriguing fact that p53 contributes to a pro-survival advantage of tumor cells under DNA damage conditions raises a critical question in radiation therapy for the 50% human cancers with intact p53 function. Herein, we reveal an anti-apoptotic role of mitochondrial p53 regulated by the cell cycle complex cyclin B1/Cdk1 in irradiated human colon cancer HCT116 cells with p53(+/+) status. Steady-state levels of p53 and cyclin B1/Cdk1 were identified in the mitochondria of many human and mouse cells, and their mitochondrial influx was significantly enhanced by radiation. The mitochondrial kinase activity of cyclin B1/Cdk1 was found to specifically phosphorylate p53 at Ser-315 residue, leading to enhanced mitochondrial ATP production and reduced mitochondrial apoptosis. The improved mitochondrial function can be blocked by transfection of mutant p53 Ser-315-Ala, or by siRNA knockdown of cyclin B1 and Cdk1 genes. Enforced translocation of cyclin B1 and Cdk1 into mitochondria with a mitochondrial-targeting-peptide increased levels of Ser-315 phosphorylation on mitochondrial p53, improved ATP production and decreased apoptosis by sequestering p53 from binding to Bcl-2 and Bcl-xL. Furthermore, reconstitution of wild-type p53 in p53-deficient HCT116 p53(-/-) cells resulted in an increased mitochondrial ATP production and suppression of apoptosis. Such phenomena were absent in the p53-deficient HCT116 p53(-/-) cells reconstituted with the mutant p53. These results demonstrate a unique anti-apoptotic function of mitochondrial p53 regulated by cyclin B1/Cdk1-mediated Ser-315 phosphorylation in p53-wild-type tumor cells, which may provide insights for improving the efficacy of anti-cancer therapy, especially for tumors that retain p53

Value of serum OPN levels in patients with acute cerebral hemorrhage for assessment of nerve function impairment

AbstractObjectiveTo study the value of serum OPN levels in patients with acute cerebral hemorrhage for assessment of neurological impairment.MethodsA total of 48 patients with cerebral hemorrhage admitted to the Emergency Department of our hospital from April 2014 to August 2015 were selected as the cerebral hemorrhage group, and 50 cases who took health examination were selected as the control group. Then, their clinical data were collected and the contents of OPN, S-100β, NSE, SOD, T-AOC and MDA were detected.ResultsThe contents of serum OPN [(24.52 ± 2.85) vs. (10.38 ± 1.25) pg/mL], S-100β [(1.77 ± 0.20) vs. (0.59 ± 0.07) pg/mL] and NSE [(24.52 ± 2.85) vs. (10.38 ± 1.25) pg/mL] in the cerebral hemorrhage group were significantly higher than those of the control group, while its SOD [(42.31 ± 5.45) vs. (67.65 ± 7.26) IU/mL] and T-AOC [(12.16 ± 1.42) vs. (20.35 ± 2.35) IU/mL] were all distinctly lower than those of the control group. The greater the amount of hemorrhage was, the more the contents of OPN [(5.75 ± 0.67) vs. (7.92 ± 0.91) vs. (10.36 ± 1.16) ng/mL], S-100β [(1.03 ± 0.12) vs. (1.79 ± 0.20) vs. (2.85 ± 0.30) pg/mL], NSE [(17.86 ± 2.14) vs. (23.94 ± 2.61) vs. (30.14 ± 3.48) pg/mL], MDA [(4.03 ± 0.51) vs. (6.18 ± 0.81) vs. (9.59 ± 1.05) nmol/mL] were and the less the contents of SOD [(52.44 ± 5.94) vs. (41.39 ± 5.26) vs. (25.52 ± 3.12) IU/mL] and T-AOC [(16.59 ± 1.83) vs. (13.04 ± 1.63) vs. (8.39 ± 0.92) IU/mL] became. The contents of serum OPN [(13.23 ± 1.63) vs. (6.95 ± 0.81) ng/mL], S-100β [(3.24 ± 0.52) vs. (0.91 ± 0.10) pg/mL], NSE [(41.32 ± 5.14) vs. (16.61 ± 1.89) pg/mL] and MDA [(11.18 ± 1.26) vs. (4.28 ± 0.54) nmol/mL] in patients with early deterioration were obviously higher than those in patients without early deterioration, while their SOD [(15.25 ± 1.79) vs. (40.59 ± 5.33) IU/mL] and T-AOC [(5.25 ± 0.77) vs. (16.25 ± 1.92) IU/mL] contents were all evidently lower. The content of serum OPN was positively associated with S-100β, NSE and MDA, but negatively correlated with SOD and T-AOC.ConclusionsThe level of serum OPN in patients with acute cerebral hemorrhage increased significantly. The level of serum OPN could estimate the bleeding volume and the severity of nerve function impairment for patients with acute cerebral hemorrhage