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1. Potential Role of Peptidylarginine Deiminase Enzymes and Protein Citrullination in Cancer Pathogenesis

Author

Sunish Mohanan, Brian D. Cherrington, Sachi Horibata, John L. McElwee, Paul R. Thompson, and Scott A. Coonrod

Subjects
Biochemistry, QD415-436
Abstract

The peptidylarginine deiminases (PADs) are a family of posttranslational modification enzymes that catalyze the conversion of positively charged protein-bound arginine and methylarginine residues to the uncharged, nonstandard amino acid citrulline. This enzymatic activity is referred to as citrullination or, alternatively, deimination. Citrullination can significantly affect biochemical pathways by altering the structure and function of target proteins. Five mammalian PAD family members (PADs 1–4 and 6) have been described and show tissue-specific distribution. Recent reviews on PADs have focused on their role in autoimmune diseases. Here, we will discuss the potential role of PADs in tumor progression and tumor-associated inflammation. In the context of cancer, increasing clinical evidence suggests that PAD4 (and possibly PAD2) has important roles in tumor progression. The link between PADs and cancer is strengthened by recent findings showing that treatment of cell lines and mice with PAD inhibitors significantly suppresses tumor growth and, interestingly, inflammatory symptoms. At the molecular level, transcription factors, coregulators, and histones are functional targets for citrullination by PADs, and citrullination of these targets can affect gene expression in multiple tumor cell lines. Next generation isozyme-specific PAD inhibitors may have therapeutic potential to regulate both the inflammatory tumor microenvironment and tumor cell growth.

Published
2012
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2. ALTERATION OF THE PKC-MEDIATED SIGNALING PATHWAY FOR SMOOTH MUSCLE CONTRACTION IN OBSTRUCTION-INDUCED HYPERTROPHY OF THE URINARY BLADDER

Author

Sunish Mohanan, Alan J. Wein, Shaohua Chang, Stephen A. Zderic, Joseph A. Hypolite, and Samuel Chacko

Subjects
Male, Indoles, 030232 urology & nephrology, Muscle Proteins, urologic and male genital diseases, Muscle hypertrophy, Potassium Chloride, Maleimides, 0302 clinical medicine, CPI-17, PKC, Phosphorylation, Protein Kinase C, 0303 health sciences, Urinary bladder, Smooth muscle contraction, female genital diseases and pregnancy complications, Urinary Bladder Neck Obstruction, medicine.anatomical_structure, bladder outlet obstruction, Tetradecanoylphorbol Acetate, Rabbits, medicine.symptom, Muscle contraction, Muscle Contraction, Signal Transduction, PDBu-induced contraction, medicine.medical_specialty, Urinary Bladder, In Vitro Techniques, Article, Pathology and Forensic Medicine, Contractility, 03 medical and health sciences, Bladder outlet obstruction, Internal medicine, medicine, Animals, Humans, Molecular Biology, Protein kinase C, 030304 developmental biology, business.industry, Urinary bladder neck obstruction, Muscle, Smooth, Cell Biology, Hypertrophy, medicine.disease, Phosphoproteins, Disease Models, Animal, Endocrinology, business
Abstract

Normal urinary bladder function requires contraction and relaxation of the detrusor smooth muscle (DSM). The DSM undergoes compensatory hypertrophy in response to partial bladder outlet obstruction (PBOO) in both men and animal models. Following bladder hypertrophy, the bladder either retains its normal function (compensated) or becomes dysfunctional (decompensated) with increased voiding frequency and decreased void volume. We analyzed the contractile characteristics of DSM in a rabbit model of PBOO. The protein kinase C (PKC) agonist phorbol 12, 13-dibutyrate (PDBu) elicited similar levels of contraction of DSM strips from normal and compensated bladders. However, PDBu-induced contraction decreased significantly in DSM strips from decompensated bladders. The expression and activity of PKC-alpha were also lowest in decompensated bladders. The PKC-specific inhibitor bisindolylmaleimide-1 (Bis) blocked PDBu-induced contraction and PKC activity in all three groups. Moreover, the phosphorylation of the phosphoprotein inhibitor CPI-17 (a 17-kDa PKC-potentiated inhibitory protein of protein phosphatase-1) was diminished in DSM from the decompensated bladder, which would result in less inhibitory potency of CPI-17 on myosin light chain phosphatase activity and contribute to less contractility. Immunostaining revealed the colocalization of PKC and phosphorylated CPI-17 in the DSM and confirmed the decreases of these signaling proteins in the decompensated bladder. Our results show a differential PKC-mediated DSM contraction with corresponding alterations of PKC expression, activity and the phosphorylation of CPI-17. Our finding suggests a significant correlation between bladder function and PKC pathway. An impaired PKC pathway appears to be correlated with severe bladder dysfunction observed in decompensated bladders.

Published
2009

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