Role for Peptidylarginine Deiminase Enzymes in Disease and Female Reproduction

Horibata, Sachi; Coonrod, Scott A.; Cherrington, Brian D.

doi:10.1262/jrd.2011-040

Cited by 55 publications

(45 citation statements)

References 67 publications

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“…Tanikawa et al have also shown that ectopic expression of PAD4 results in inhibition of tumor cell growth [27]. Aside from PAD4, we also found that PAD2 localizes to mammary tissues and is dysregulated in breast cancer [28–31]. Unlike PAD4, we observed that PAD2 seems to be involved in promoting breast cancer progression [30, 32].…”

Section: Introductionsupporting

confidence: 55%

Role of peptidylarginine deiminase 2 (PAD2) in mammary carcinoma cell migration

et al. 2017

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BackgroundPenetration of the mammary gland basement membrane by cancer cells is a crucial first step in tumor invasion. Using a mouse model of ductal carcinoma in situ, we previously found that inhibition of peptidylarginine deiminase 2 (PAD2, aka PADI2) activity appears to maintain basement membrane integrity in xenograft tumors. The goal of this investigation was to gain insight into the mechanisms by which PAD2 mediates this process.MethodsFor our study, we modulated PAD2 activity in mammary ductal carcinoma cells by lentiviral shRNA-mediated depletion, lentiviral-mediated PAD2 overexpression, or PAD inhibition and explored the effects of these treatments on changes in cell migration and cell morphology. We also used these PAD2-modulated cells to test whether PAD2 may be required for EGF-induced cell migration. To determine how PAD2 might promote tumor cell migration in vivo, we tested the effects of PAD2 inhibition on the expression of several cell migration mediators in MCF10DCIS.com xenograft tumors. In addition, we tested the effect of PAD2 inhibition on EGF-induced ductal invasion and elongation in primary mouse mammary organoids. Lastly, using a transgenic mouse model, we investigated the effects of PAD2 overexpression on mammary gland development.ResultsOur results indicate that PAD2 depletion or inhibition suppresses cell migration and alters the morphology of MCF10DCIS.com cells. In addition, we found that PAD2 depletion suppresses the expression of the cytoskeletal regulatory proteins RhoA, Rac1, and Cdc42 and also promotes a mesenchymal to epithelial-like transition in tumor cells with an associated increase in the cell adhesion marker, E-cadherin. Our mammary gland organoid study found that inhibition of PAD2 activity suppresses EGF-induced ductal invasion. In vivo, we found that PAD2 overexpression causes hyperbranching in the developing mammary gland.ConclusionTogether, these results suggest that PAD2 plays a critical role in breast cancer cell migration. Our findings that EGF treatment increases protein citrullination and that PAD2 inhibition blocks EGF-induced cell migration suggest that PAD2 likely functions within the EGF signaling pathway to mediate cell migration.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3354-x) contains supplementary material, which is available to authorized users.

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Section: Introductionsupporting

confidence: 55%

Role of peptidylarginine deiminase 2 (PAD2) in mammary carcinoma cell migration

et al. 2017

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“…Furthermore, analysis of cDNA microarray data from Hewitt et al shows that PAD1, 2, and 4 mRNA appear to be estrogen regulated [44]. In the uterus, the distribution of these isozymes appears to be primarily limited to glandular and luminal epithelial cells and also displays an estrous cycle-dependent regulation pattern, with the highest expression of these family members occurring during estrus [45, 46]. Similar to the pituitary, PAD2 and PAD4 expression and activity in the uterus is lost following ovariectomy, but can be restored by injection of exogenous estrogen, indicative of estrogen regulation [45, 46].…”

Section: Hormonal Regulation Of Padsmentioning

confidence: 99%

“…In the uterus, the distribution of these isozymes appears to be primarily limited to glandular and luminal epithelial cells and also displays an estrous cycle-dependent regulation pattern, with the highest expression of these family members occurring during estrus [45, 46]. Similar to the pituitary, PAD2 and PAD4 expression and activity in the uterus is lost following ovariectomy, but can be restored by injection of exogenous estrogen, indicative of estrogen regulation [45, 46]. Given the known mitogenic properties of estrogen in female cancers, it is possible that estrogen-induced upregulation of PAD expression and activity in the uterus may promote neoplastic growth in this tissue.…”

Section: Hormonal Regulation Of Padsmentioning

confidence: 99%

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

Mohanan

Cherrington

Horibata

et al. 2012

Biochemistry Research International

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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.

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“…Posttranslational protein citrullination leads to drastic changes on protein charge, structure, and function (12,15,42). Of the five known subtypes of PAD (PAD1, PAD2, PAD3, PAD4, and PAD6), PAD4 is the only PAD enzyme localized in the nucleus and is the only PAD protein detected in the kidney (39,41).…”

mentioning

confidence: 99%

Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury

Ham

Rabadi

Kim

et al. 2014

American Journal of Physiology-Renal Physiology

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Peptidyl arginine deiminase (PAD)4 is a nuclear enzyme that catalyzes the posttranslational conversion of arginine residues to citrulline. Posttranslational protein citrullination has been implicated in several inflammatory autoimmune diseases, including rheumatoid arthritis, colitis, and multiple sclerosis. Here, we tested the hypothesis that PAD4 contributes to ischemic acute kidney injury (AKI) by exacerbating the inflammatory response after renal ischemia-reperfusion (I/R). Renal I/R injury in mice increased PAD4 activity as well as PAD4 expression in the mouse kidney. After 30 min of renal I/R, vehicle-treated mice developed severe AKI with large increases in plasma creatinine. In contrast, mice pretreated with PAD4 inhibitors (2-chloroamidine or streptonigrin) had significantly reduced renal I/R injury. Further supporting a critical role for PAD4 in generating ischemic AKI, mice pretreated with recombinant human PAD4 (rPAD4) protein and subjected to mild (20 min) renal I/R developed exacerbated ischemic AKI. Consistent with the hypothesis that PAD4 regulates renal tubular inflammation after I/R, mice treated with a PAD4 inhibitor had significantly reduced renal neutrophil chemotactic cytokine (macrophage inflammatory protein-2 and keratinocyte-derived cytokine) expression and had decreased neutrophil infiltration. Furthermore, mice treated with rPAD4 had significantly increased renal tubular macrophage inflammatory protein-2 and keratinocyte-derived cytokine expression as well as increased neutrophil infiltration and necrosis. Finally, cultured mouse kidney proximal tubules treated with rPAD4 had significantly increased proinflammatory chemokine expression compared with vehicle-treated cells. Taken together, our results suggest that PAD4 plays a critical role in renal I/R injury by increasing renal tubular inflammatory responses and neutrophil infiltration after renal I/R.

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Role for Peptidylarginine Deiminase Enzymes in Disease and Female Reproduction

Cited by 55 publications

References 67 publications

Role of peptidylarginine deiminase 2 (PAD2) in mammary carcinoma cell migration

Role of peptidylarginine deiminase 2 (PAD2) in mammary carcinoma cell migration

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

Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury

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