This process is tightly regulated by the rates of myosin light chain phosphorylation through the myosin light chain kinase and subsequent dephosphorylation via myosin phosphatase (MLCP) 2 (1-6). MLCP is a heterotrimer comprised of a 130-kDa myosin binding subunit (MBS), a 37-kDa protein phosphatase inhibitor catalytic subunit, and a 20-kDa subunit with no ascribed function (1-5). The importance of cGMP-dependent PKG-I␣ in vascular smooth muscle tone is supported by extensive studies demonstrating that PKG-I␣ regulates pathways of NO-dependent vascular relaxation that involve the MBS of MLCP (6). Protein-protein interactions between PKG-I␣ and MLCP are believed to be mediated by the N-terminal leucine zipper (LZ) domain of 59 residues in PKG-I␣ (PKG-I␣ 1-59 ) and C-terminal 180 residues of MBS (MBS CT180 ) in MLCP (1).In previous studies by Atkinson et al. (7), they described the dimer properties of PKG-I␣ (residues 1-39) and determined the structure of the PKG-I␣ monomer within this leucine-zipper dimer. We and others have shown that N-terminal PKG-I␣ is a homodimer in solution (7-9). Recently we have demonstrated that the LZ region of PKG-I␣, PKG-I␣ 1-59 , is indeed a coiled coil (CC) LZ dimer of ϳ38 residues commencing at residue Ala 9 and extending through to Gln 44 on the basis of our 15 N R 1 and R 2 relaxation data (10). Our NMR structure of this region of PKG-I␣ was determined using residual dipolar couplings as structural restraints, whereas the parallel orientation of this homodimer was determined using Prediction of Alignment from Structure (PALES), a method that evaluates the structural charge distribution of the monomer and dimer structures (10).The interaction between PKG-I␣ 1-59 and the CC and/or LZ domain of MBS CT180 has recently been documented by several workers (8,11,12). MBS CT180 is comprised of a predicted bind-
Purpose: Proteomic profiling of patients undergoing intensity-modulated radiotherapy (IMRT) for prostate cancer can identify unique biomarkers that reflect acute toxicity in normal tissues. Our objectives were to measure inflammatory cytokine proteins during IMRT and assess the variability of individual proteomic signatures. Experimental Design: Forty-two patients with intermediate-risk prostate cancer were recruited as follows: group 1, definitive IMRT (78 Gy in 39 fractions, n = 22), and group 2, IMRT postprostatectomy (66 Gy in 33 fractions, n = 20). Blood/urine samples were collected at baseline and weekly during IMRT. Acute toxicity was graded weekly during radiotherapy using CTC-AE v3.0 criteria. Multiplexed immunoassays were used to quantify cytokines including granulocyte macrophage colony-stimulating factor, IFN-γ, tumor necrosis factor-α, interleukin (IL)-1α, IL-2, IL6, IL-8, IL-10, and IL-12p70. Results: We observed positive correlations between cytokine expression between serum and plasma, but not between serum/plasma and urine. The Mann-Whitney test showed a significant increase in IFN-γ and IL-6 during IMRT (P = 0.0077, 0.0035). Increasing IL-2 and IL-1 expression were associated with increased probability of acute gastrointestinal and genitourinary toxicity, respectively. Conclusions: Determination of radiation-response signatures is feasible using multiplexed immunoassays and is a promising predictive early biomarker of toxicity outcomes. (Clin Cancer Res 2009;15(17):5576-83) Cellular damage caused by ionizing radiation induces specific proteins involved in DNA repair, cell death, inflammation, and other pathophysiologic responses (1). The majority of biomarker studies in radiation oncology have focused on predicting tumor response and survival (2). Clinically, the acute toxicity of prostate cancer radiotherapy manifest as gastrointestinal and genitourinary symptoms based on validated scoring criteria, [e.g., Common Terminology Criteria for Adverse Events (CTC-AE); ref. 3]. Radiotherapy dose escalation using intensity-modulated radiotherapy (IMRT) is associated with improved biochemical tumor control, yet still has radiation-induced toxicity. Dose-dependent markers of acute normal toxicity could help predict individuals at increased risk of radiotherapy-related injury and help to maximize the therapeutic ratio for individual patients.Rubin and colleagues were among the first to describe the role of cytokines (small glycoproteins involved in intercellular signaling) in mediating radiation toxicity (4). They showed in preclinical and clinical lung studies that levels of interleukin (IL)-1, transforming growth factor (TGF)-β, and tumor necrosis factor (TNF)-α were increased immediately after radiation exposure, and that chronically elevated TGF-β levels were associated with increased risk of pulmonary fibrosis. The link between radiation toxicity and cytokine expression is supported by studies showing that prolonged cytokine expression postradiotherapy is correlated to specific lung radi...
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