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Role of Homeostatic Changes in Salivary Gland Acinar Cells in Primary Sjögren's Syndrome: A Review
J Oral Med Pain 2023;48:39-44
Published online June 30, 2023;  https://doi.org/10.14476/jomp.2023.48.2.39
© 2023 Korean Academy of Orofacial Pain and Oral Medicine

Jin-Seok Byun

Department of Oral Medicine, School of Dentistry, Kyungpook National University, Daegu, Korea
Correspondence to: Jin-Seok Byun
Department of Oral Medicine, School of Dentistry, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Korea
E-mail: jsbyun@knu.ac.kr
https://orcid.org/0000-0002-6182-1238
Received June 7, 2023; Revised June 13, 2023; Accepted June 14, 2023.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Primary Sjögren's syndrome (pSS) is an autoimmune progressive disease characterized by dysfunction and inflammation of the salivary glands. The underlying mechanisms of salivary gland involvement in pSS remain unclear, and researchers have primarily focused on immunological phenomena, making it difficult to distinguish between the cause and effect of the disease. Consequently, our research aims to directly investigate changes in homeostasis occurring in acinar cells, specifically in the context of muscarinic signaling, mucins, aquaporins, and forkhead box protein O1, to elucidate the initial step of pSS. We compare the disease-related phenomena observed in salivary gland acinar cells in pSS with the overall process of salivary secretion.
Keywords : Aquaporins; Forkhead box protein O1; Mucins; Muscarinic signaling; Primary Sjögren’s syndrome; Salivary gland acinar cells
INTRODUCTION

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease characterized by dysfunction and inflammation of the exocrine glands, particularly the salivary and lacrimal glands [1]. This condition can result in reduced production of saliva and tears, leading to symptoms such as dry mouth and eyes. During the progression of Sjögren's syndrome, the immune system mistakenly attacks the moisture-producing glands, causing inflammation, and damage to the glandular tissue. Among the various signs and symptoms, oral dryness is one of representative symptom observed in patients with pSS. In this context, a particularly important diagnostic indicator is the positive infiltrating lymphocyte score in salivary gland biopsy [2,3].

The salivary glands are a major target organ in the progression of pSS [4]. To gain a comprehensive understanding of salivary gland dysfunctions in pSS, it is crucial to investigate the role of the main saliva producers, known as the salivary epithelia. The salivary gland epithelium is the layer of cells that lines the salivary glands. It consists of various epithelial cell types, which perform specific functions in the production, modification, and secretion of saliva. The cell types in the salivary gland epithelium include acinar, ductal, and myoepithelial cells. Of these, acinar cells are found in the acini of the salivary glands and are responsible for synthesizing and secreting primary saliva. Acinar cells produce saliva by actively transporting ions, such as sodium, and potassium, across their cell membranes. They also secrete enzymes, proteins, and other substances that contribute to the composition of saliva. Ductal cells receive primary saliva from the acinar cells, modifying its composition before its secretion into the oral cavity. Myoepithelial cells function as machinery for the contraction of acini.

Salivary gland epithelial cells have been considered not only as passive bystanders in excessive immune-mediated organ failures but also as key cells associated with disease progression [5,6]. Among the salivary epithelial components, acinar cells have been studied extensively in the context of disease progression. Compared with normal salivary gland acinar cells (SGACs), dysfunctional SGACs in pSS exhibit several structural and functional abnormalities, including reduced neurotransmission, abnormal intracellular metabolic procedures, distorted secretion of salivary components, and even the production of proinflammatory cytokines [6,7]. Although the cause and effect of these changes are still under debate, elucidating the underlying mechanism will help researchers understand and overcome the disease. In this review, we discuss the changes in SGACs in Sjögren's syndrome and their importance in relation to decreased salivary production and proinflammatory consequences.

ABNORMALITY OF SALIVARY GLAND ACINAR CELLS

SGACs are the primary functional parenchymal cells responsible for producing primary saliva in the salivary glands. These cells constitute the majority of the glandular tissue and play a crucial role in saliva production. SGACs can be classified as serous or mucous based on the type of saliva they produce. They possess specialized structures and functions that optimize saliva production. A series of processes within the acinar tissue are essential for optimal salivary secretion, including 1) maintaining a normal morphological structure, 2) responding to parasympathetic salivation signaling, 3) producing secretory granules, and 4) facilitating saliva production and transport to the lumen. In this section, we will explore the pathological phenomena observed in Sjögren's syndrome acinar cells in relation to these processes. The graphical abstract associated with this section is presented in Fig. 1.

1. Morphological Distortion

The glands of patients with pSS exhibit a disorganized basal membrane and atrophy in SGACs. Research has indicated that the observed distortion of the basement membrane in acinar cells with pSS is primarily associated with laminin and type IV collagen [8]. Changes in laminin distribution in the basement membrane of acinar cells can serve as an indicator of the progression of Sjögren's syndrome, as changes in laminin expression levels can be observed prior to excessive lymphocyte infiltration [9]. In terms of glandular acinar atrophy, the absence of laminin α chains and alpha 1 may impair the ability of progenitor cells to differentiate into acinar cells, resulting in acini atrophy and ductal cell hyperplasia [10]. Researchers have also focused on the activity of matrix metalloproteinases, which may be linked to remarkable changes in the structural organization of the basal lamina and apical surface of acini in patients with Sjögren's syndrome [11].

Morphological changes observed in the acinar cells of individuals with pSS include cytoplasmic accumulation of lipid droplets and swollen mitochondria [12]. Mitochondria play a crucial role in cellular physiology, multiple signaling pathways, and cell metabolism. Moreover, their morphological changes can be contributing factors to various pathological symptoms observed in pSS, such as epithelial autophagy, and autoantibody expression.

2. Reduced Muscarinic Salivation Signaling

Muscarinic signaling plays a vital role in the functioning of acinar cells in the salivary glands, and alterations in this signaling pathway have been implicated in pSS. Muscarinic receptors are G protein–coupled receptors found in various tissues. They are primarily activated by the neurotransmitter acetylcholine and are involved in mediating the effects of the parasympathetic nervous system. When acetylcholine binds to muscarinic receptors, it initiates a series of intracellular signaling events that can have diverse physiological effects depending on the tissue and receptor subtype. There are five subtypes of muscarinic receptors, namely M1-M5, which are distributed in different tissues and cell types. Among these subtypes, the M3 receptor is primarily expressed in salivary glands and plays a crucial role in primary salivation. Activation of the acetylcholine–M3 receptor interaction induces phospholipase C activation, leading to the degradation of phosphatidylinositol 4,5-bisphosphate into inositol trisphosphate and diacylglycerol, which in turn results in an increased intracellular Ca2+ concentration. The increased cytosolic Ca2+ concentration opens apical chloride channels and basolateral potassium channels, facilitating primary saliva production [13]. Additionally, activation of the M3 receptor triggers the trafficking of aquaporin (AQP) 5 from the cytoplasm to the apical membrane, enabling rapid water transport across the cell membrane [14].

Studies have demonstrated a decrease in the expression levels of M3 receptors in the salivary glands of patients with pSS compared with healthy individuals. This reduction in M3 receptor expression can contribute to impaired glandular function and decreased saliva production, as observed in patients with pSS [15]. Furthermore, pSS is characterized by the presence of autoantibodies targeting M3 receptors, potentially affecting their function and exacerbating glandular dysfunction [14,16]. Moreover, intracellular signaling pathways downstream of muscarinic receptors in pSS can be dysregulated, leading to impaired secretion of fluid, electrolytes, and other components of saliva by acinar cells.

3. Aberrant Mucin Localization and Proinflammatory Cytokine Secretion

For normal saliva functioning, the composition of salivary proteins is important, in addition to water volume. Salivary proteins, including mucins, enzymes, antibodies, and immunoglobulins, as well as proline-rich proteins and statherin, serve different functions, and properties. Mucins, belonging to the mucin family are large, heavily glycosylated proteins. Salivary mucins are secreted from the apical pole of acinar cells and contribute to the viscoelastic properties of saliva, providing oral cavity lubrication, moistening, and protection. Changes in salivary mucins can affect oral health, as alterations in mucin composition and/or function may contribute to dry mouth (xerostomia), which leads to difficulties in chewing, swallowing, and increased susceptibility to dental caries and oral infections.

Changes in salivary mucins have been observed in Sjögren's syndrome, contributing to the characteristic dry mouth and other symptoms experienced by patients with the condition. Changes in salivary mucins in patients with Sjögren's syndrome are multifactorial and can be influenced by various underlying factors. including decreased mucin production, altered mucin composition, and abnormal mucin distribution, and clearance. Several studies have hypothesized changes in the amount or composition of mucins in the saliva of patients with pSS. However, most of these studies did not confirm significant differences compared with healthy individuals [17,18]. Instead, researchers found that the distribution of mucins, such as mucin-5B (MUC5B), MUC7, and MUC1, in the salivary gland acinar cells of patients with Sjögren's syndrome was altered compared with that in normal populations. In Sjögren's syndrome, the salivary mucin components MUC5B and MUC7 are localized adjacent to the apical pole [19,20]. Mislocalized mucins are partially transported outside the membrane, where they can activate toll-like receptor 4, resulting in autocrine production of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 [19]. Interestingly, an overload of MUC1 in the acinar cells of patients with Sjögren's syndrome may induce an apoptosis-like phenotype [19,21]. Collectively, these findings suggest that mislocalized mucins can create an inflammatory environment in the salivary glands of patients with Sjögren's syndrome, leading to cellular stress, and even cell death.

4. Disorganized AQPs

AQPs, a family of membrane proteins that play a critical role in facilitating the movement of water and other small molecules across cell membranes, play a crucial role in SGACs by facilitating water transport across their membranes. Thirteen different isoforms of AQPs are known to exist [22]. In human salivary glands, AQP1 is expressed on myoepithelial cells, AQP3 is present within the basal membrane of acinar cells, and AQP5 is located in the apical membrane of acinar cells [23]. Reduced levels or altered distribution of AQPs can impair water transport and contribute to decreased saliva production, resulting in the characteristic dry mouth observed in pSS. Several studies have emphasized the importance of AQPs in Sjögren's syndrome. For example, decreased AQP1 expression and the presence of anti-AQP1 autoantibodies have been reported in the salivary glands of patients with Sjögren's syndrome [24,25]. However, AQP1 deficiency was found to have no observable effect on saliva production [26], and anti-AQP1 autoantibodies have not been associated with a reduced salivary flow rate [25]. Regarding AQP3, although its expression was found to increase and decrease in the apical and basolateral sides, respectively, of salivary gland acini in a Sjögren's syndrome group compared with a normal control group [27], it remains unclear whether this phenotype is a result or a cause of Sjögren's syndrome. Therefore, further studies are necessary to better understand the precise roles of AQP1 and AQP3 in salivary hypofunction occurring in patients with Sjögren's syndrome.

The role of AQP5 in SGACs under pSS is relatively well-defined. The presence of autoantibodies to AQP5 in the serum of patients with Sjögren's syndrome has been confirmed [28], and systematic studies have revealed the abnormal intracellular localization of AQP5 [29-31], including a study incorporating AQP5-targeted gene therapy in a Sjögren's syndrome animal model [32]. Typically, AQP5 is localized to the apical or luminal membranes of acinar cells in the salivary glands, where it facilitates the movement of water across these membranes. However, in Sjögren's syndrome, AQP5 can exhibit abnormal distribution patterns within the affected glands. In the acinar cells of patients with Sjögren's syndrome, the normal apical distribution of AQP5 is reduced and shifted toward the periphery, basal membrane, or into the cytoplasm [27,33]. This abnormal localization may be a consequence of the inflammatory process and immune cell infiltration in the glands. The mechanisms underlying the mislocalization of AQP5 in Sjögren's syndrome are not fully understood, but they are believed to involve various factors, including autoantibodies, and proinflammatory cytokines. Animal experiments have revealed that altered AQP5 protein levels may be related to the degree of inflammatory response [34]. Patients diagnosed with pSS exhibit the presence of major inflammatory cytokines, including type 1 interferons, IL-1β, interleukin-17, TNF-α, and B-cell activating factor [35-37]. Given that the activation of muscarinic and adrenergic receptors plays a primary role in the translocation of AQP5, the aberrant localization of AQP5 might be part of defective muscarinic M3 receptor signaling or altered intracellular protein interactions associated with AQP5.

FORKHEAD BOX O1 (FOXO1) AS A DIRECT REGULATOR OF AQP5

In our previous study entitled “Function of FoxO1 as a key regulating factor for AQP5”, the authors provided insights into the decreased expression of AQP5 in the salivary gland of patients with Sjögren's syndrome [38]. FoxO1 is an abbreviation of Forkhead box protein O1, a protein that is well-known for its various physiological regulatory functions, including vascular growth, oxidative stress, and metabolism [39-41]. In the aforementioned study, the authors initially established a correlation between FoxO1 expression and decreased AQP5 gene and protein expression in the minor salivary glands of patients with Sjögren's syndrome. Subsequently, they confirmed these findings using rat submandibular gland cell line C6 in loss- and gain-of-function experiments. The authors found that FoxO1 can bind directly to the promoter region of AQP5, providing a clear explanation for the reduced salivation observed in patients with Sjögren's syndrome independent of autoimmune inflammatory consequences. Their study is significant because it not only reconfirms the reduced expression of AQP5 in the salivary gland under Sjögren's syndrome but also reveals the novel role of FoxO1 as a direct upstream regulator associated with AQP5-mediated reduction in salivary secretion. The graphical abstract of this study is shown in Fig. 2.

CONCLUSION

Salivary gland dysfunction is a prevalent clinical manifestation of Sjögren's syndrome. While genetic factors predominantly influence susceptibility to the syndrome, it is crucial to acknowledge the involvement of various signaling pathways, systems, and processes in its disease progression. Although the relative significance of these factors during disease onset and progression remains unclear, dysregulation of acinar cell functional machinery is a key contributor to the homeostatic imbalance observed in pSS. This review emphasizes the pivotal role of SGACs, providing insights into their involvement not only as passive bystanders in immune-mediated organ failure but also as key mediators associated with disease initiation and progression.

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

DATA AVAILABILITY STATEMENT

The datasets used in the current study are available from the corresponding author upon reasonable request.

FUNDING

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) RS-2023-00208416.

Figures
Fig. 1. Abnormalities in salivary gland acinar cells.
Fig. 2. Decreased FoxO1 expression directly affects the downregulation of AQP5 expression. AQP, aquaporin; FoxO1, forkhead box O1; TSS, transcription start site.
References
  1. Brito-Zeron P, Baldini C, Bootsma H, et al. Sjögren syndrome. Nat Rev Dis Primers 2016;2:16047.
    Pubmed CrossRef
  2. Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome: a consensus and data-driven methodology involving three international patient cohorts. Ann Rheum Dis 2017;76:9-16.
    Pubmed CrossRef
  3. Shiboski SC, Shiboski CH, Criswell L, et al. American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012;64:475-87.
    Pubmed KoreaMed CrossRef
  4. Aqrawi LA, Jensen JL, Oijordsbakken G, et al. Signalling pathways identified in salivary glands from primary Sjögren's syndrome patients reveal enhanced adipose tissue development. Autoimmunity 2018;51:135-146.
    Pubmed CrossRef
  5. Tsunawaki S, Nakamura S, Ohyama Y, et al. Possible function of salivary gland epithelial cells as nonprofessional antigen-presenting cells in the development of Sjögren's syndrome. J Rheumatol 2002;29:1884-1896.
  6. Tang Y, Zhou Y, Wang X, et al. The role of epithelial cells in the immunopathogenesis of Sjögren's syndrome. J Leukoc Biol 2023;qiad049.
    Pubmed CrossRef
  7. Verstappen GM, Pringle S, Bootsma H, Kroese FGM. Epithelial-immune cell interplay in primary Sjogren syndrome salivary gland pathogenesis. Nat Rev Rheumatol 2021;17:333-348.
    Pubmed KoreaMed CrossRef
  8. Molina C, Alliende C, Aguilera S, et al. Basal lamina disorganisation of the acini and ducts of labial salivary glands from patients with Sjogren's syndrome: association with mononuclear cell infiltration. Ann Rheum Dis 2006;65:178-183.
    Pubmed KoreaMed CrossRef
  9. McArthur CP, Fox NW, Kragel P. Monoclonal antibody detection of laminin in minor salivary glands of patients with Sjögren's syndrome. J Autoimmun 1993;6:649-661.
    Pubmed CrossRef
  10. Nikolov NP, Illei GG. Pathogenesis of Sjögren's syndrome. Curr Opin Rheumatol 2009;21:465-470.
    Pubmed KoreaMed CrossRef
  11. Perez P, Goicovich E, Alliende C, et al. Differential expression of matrix metalloproteinases in labial salivary glands of patients with primary Sjögren's syndrome. Arthritis Rheum 2000;43:2807-2817.
    Pubmed CrossRef
  12. Li N, Li YS, Hu JW, et al. A link between mitochondrial dysfunction and the immune microenvironment of salivary glands in primary Sjogren's syndrome. Front Immunol 2022;13:845209.
    Pubmed KoreaMed CrossRef
  13. Dawson L, Tobin A, Smith P, Gordon T. Antimuscarinic antibodies in Sjögren's syndrome: where are we, and where are we going? Arthritis Rheum 2005;52:2984-2995.
    Pubmed CrossRef
  14. Li J, Ha YM, Ku NY, et al. Inhibitory effects of autoantibodies on the muscarinic receptors in Sjögren's syndrome. Lab Invest 2004;84:1430-1438.
    Pubmed CrossRef
  15. Matsui M, Motomura D, Karasawa H, et al. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci U S A 2000;97:9579-9584.
    Pubmed KoreaMed CrossRef
  16. Lee BH, Gauna AE, Perez G, et al. Autoantibodies against muscarinic type 3 receptor in Sjögren's syndrome inhibit aquaporin 5 trafficking. PLoS One 2013;8:e53113.
    Pubmed KoreaMed CrossRef
  17. Chaudhury NM, Proctor GB, Karlsson NG, Carpenter GH, Flowers SA. Reduced mucin-7 (Muc7) sialylation and altered saliva rheology in Sjögren's syndrome associated oral dryness. Mol Cell Proteomics 2016;15:1048-1059.
    Pubmed KoreaMed CrossRef
  18. Chaudhury NMA, Shirlaw P, Pramanik R, Carpenter GH, Proctor GB. Changes in saliva rheological properties and mucin glycosylation in dry mouth. J Dent Res 2015;94:1660-1667.
    Pubmed CrossRef
  19. Barrera MJ, Aguilera S, Veerman E, et al. Salivary mucins induce a toll-like receptor 4-mediated pro-inflammatory response in human submandibular salivary cells: are mucins involved in Sjögren's syndrome? Rheumatology (Oxford) 2015;54:1518-1527.
    Pubmed CrossRef
  20. Barrera MJ, Sanchez M, Aguilera S, et al. Aberrant localization of fusion receptors involved in regulated exocytosis in salivary glands of Sjögren's syndrome patients is linked to ectopic mucin secretion. J Autoimmun 2012;39:83-92.
    Pubmed CrossRef
  21. Castro I, Albornoz N, Aguilera S, et al. Aberrant MUC1 accumulation in salivary glands of Sjögren's syndrome patients is reversed by TUDCA in vitro. Rheumatology (Oxford) 2020;59:742-753.
    Pubmed CrossRef
  22. Morishita Y, Sakube Y, Sasaki S, Ishibashi K. Molecular mechanisms and drug development in aquaporin water channel diseases: aquaporin superfamily (superaquaporins): expansion of aquaporins restricted to multicellular organisms. J Pharmacol Sci 2004;96:276-279.
    Pubmed CrossRef
  23. Gresz V, Kwon TH, Hurley PT, et al. Identification and localization of aquaporin water channels in human salivary glands. Am J Physiol Gastrointest Liver Physiol 2001;281:G247-254.
    Pubmed CrossRef
  24. Beroukas D, Hiscock J, Gannon BJ, Jonsson R, Gordon TP, Waterman SA. Selective down-regulation of aquaporin-1 in salivary glands in primary Sjogren's syndrome. Lab Invest 2002;82:1547-1552.
    Pubmed CrossRef
  25. Alam J, Choi YS, Koh JH, et al. Detection of Autoantibodies against Aquaporin-1 in the Sera of Patients with Primary Sjogren's Syndrome. Immune Netw 2017;17:103-109.
    Pubmed KoreaMed CrossRef
  26. Verkman A, Yang B, Song Y, Manley GT, Ma T. Role of water channels in fluid transport studied by phenotype analysis of aquaporin knockout mice. Exp Physiol 2000;85 Spec No:233S-241S.
    Pubmed CrossRef
  27. Ichiyama T, Nakatani E, Tatsumi K, et al. Expression of aquaporin 3 and 5 as a potential marker for distinguishing dry mouth from Sjögren's syndrome. J Oral Sci 2018;60:212-220.
    Pubmed CrossRef
  28. Alam J, Koh JH, Kim N, et al. Detection of autoantibodies against aquaporin-5 in the sera of patients with primary Sjögren's syndrome. Immunol Res 2016;64:848-856.
    Pubmed KoreaMed CrossRef
  29. Soyfoo MS, De Vriese C, Debaix H, et al. Modified aquaporin 5 expression and distribution in submandibular glands from NOD mice displaying autoimmune exocrinopathy. Arthritis Rheum 2007;56:2566-2574.
    Pubmed CrossRef
  30. Steinfeld S, Cogan E, King LS, Agre P, Kiss R, Delporte C. Abnormal distribution of aquaporin-5 water channel protein in salivary glands from Sjögren's syndrome patients. Lab Invest 2001;81:143-148.
    Pubmed CrossRef
  31. Enger TB, Aure MH, Jensen JL, Galtung HK. Calcium signaling and cell volume regulation are altered in Sjögren's syndrome. Acta Odontol Scand 2014;72:549-556.
    Pubmed CrossRef
  32. Lai Z, Yin H, Cabrera-Perez J, et al. Aquaporin gene therapy corrects Sjogren's syndrome phenotype in mice. Proc Natl Acad Sci U S A 2016;113:5694-5699.
    Pubmed KoreaMed CrossRef
  33. Enger TB, Aure MH, Jensen JL, Galtung HK. Calcium signaling and cell volume regulation are altered in Sjogren's Syndrome. Acta Odontol Scand 2014;72:549-556.
    Pubmed CrossRef
  34. Soyfoo MS, Konno A, Bolaky N, et al. Link between inflammation and aquaporin-5 distribution in submandibular gland in Sjögren's syndrome? Oral Dis 2012;18:568-574.
    Pubmed CrossRef
  35. Sandhya P, Theyilamannil Kurien B, Danda D, Hal Scofield R. Update on pathogenesis of Sjogren's syndrome. Curr Rheumatol Rev 2017;13:5-22.
    Pubmed KoreaMed CrossRef
  36. Argyropoulou OD, Valentini E, Ferro F, et al. One year in review 2018: Sjögren's syndrome. Clin Exp Rheumatol 2018;36 Suppl 112:14-26.
  37. Verstappen GM, Corneth OB, Bootsma H, Kroese FG. Th17 cells in primary Sjögren's syndrome: pathogenicity and plasticity. J Autoimmun 2018;87:16-25.
    Pubmed CrossRef
  38. Lee SM, Lee SW, Kang M, et al. FoxO1 as a Regulator of Aquaporin 5 Expression in the Salivary Gland. J Dent Res 2021;100:1281-1288.
    Pubmed CrossRef
  39. Hosaka T, Biggs WH 3rd, Tieu D, et al. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci U S A 2004;101:2975-2980.
    Pubmed KoreaMed CrossRef
  40. Tothova Z, Kollipara R, Huntly BJ, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007;128:325-339.
    Pubmed CrossRef
  41. Puig O, Tjian R. Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev 2005;19:2435-2446.
    Pubmed KoreaMed CrossRef


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