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• W2034451334 abstract "The pancreas is a complex organ composed of an exocrine component that is essential for nutrient digestion and an endocrine component that is critical for the regulation of glucose homeostasis. The endocrine portion, which represents only ∼2% of the pancreas, is made up of groups of endocrine cells called the islets of Langerhans. Each islet is composed of at least five types of cells, including the insulin-producing β-cells (65–80%) (1), the glucagon-releasing α-cells (15–20%) (2), the somatostatin-producing δ-cells (3–10%) (3), the pancreatic polypeptide-containing PP cells (1%) (4), and the ghrelin-containing ɛ-cells (<1%) (5). Dysfunction of the pancreas can impact either the endocrine or the endocrine components and lead to the development of two important diseases worldwide today, namely, diabetes mellitus or pancreatic cancer, respectively. Diabetes mellitus is classified into type 1 diabetes (T1D) and type 2 diabetes (T2D) as well as monogenic forms termed maturity-onset diabetes of the young (MODY). T1D is prevalent in children and adolescents and is characterized by absolute deficiency of insulin, secondary to autoimmune destruction of the β-cells by autologous cytotoxic T-cells. In contrast, T2D is usually diagnosed in adults and its prevalence increases with age, although alarming recent data indicate that symptoms that characterize T2D also occur in adolescents (6). T2D is characterized by insulin resistance in the canonical insulin-sensitive tissues including adipose, skeletal muscle, and liver. MODY was originally diagnosed in individuals below the age of 25 yr with an autosomal dominant inheritance (6). The underlying defects in MODY are mutations in the genes coding for transcription factors that are essential for β-cell development/differentiation and glucose-sensing proteins. Hepatic nuclear factors (HNFs) comprise a family of transcription factors that play an important role in the modulation of β-cell differentiation and/or function. Mutations in the HNFs have been associated with MODY – for example, mutations in HNF4α cause MODY1 (7), mutations in HNF1α cause MODY3 (8), and mutations in HNF1β cause MODY5 (9). Mutations in the gene coding for insulin-promoting factor/pancreatic and duodenal homeobox 1 (PDX1) or NeuroD have been liked to MODY4 and MODY6, respectively (10, 11). A mutation in the glucokinase gene, which is essential for glucose sensing, is the underlying defect in MODY2, the most common of all forms of MODY (12, 13). More recently, new genes associated with diabetes have been identified and include carboxyl ester lipase (14) and the insulin gene itself (15). Almost 6% of the world’s population suffers from diabetes with a total prevalence reaching 171 million individuals including 20.8 million in the USA alone (census reports in 2005, www.cdc.gov/diabetes) (16). Wild et al. have predicted that the total number of individuals with diabetes will rise to a staggering 366 million in less than 30 yr if preventive action is not undertaken immediately (16, 17). Pancreatic cancer, which largely afflicts the exocrine pancreas, is the fourth most common cause of cancer deaths in the USA and affects ∼28 000 individuals annually (18). Both diabetes and cancer lead to pancreatic islet dysfunction that includes altered islet growth/apoptosis and hormonal secretion defects. A thorough understanding of the mechanisms that underlie these disorders is critical to plan therapeutic approaches to treat each pathological state. Despite significant progress in understanding the pathophysiology of diabetes and pancreatic cancer, the key regulators and signaling proteins involved in the two processes that allow an effective therapeutic approach are still elusive. This review will focus on recent work related to key regulators of islet/β-cell regeneration with an emphasis on growth factor signaling. We will provide a short overview on insulin and glucagon processing and secretion and also review the current state of knowledge on the impact of aging on islet biology and discuss the potential for pancreatic cell progenitors in islet cell regeneration. Pancreatic β-cells are remarkably dynamic cells that are able to adapt and modulate their mass in response to a variety of physiological (pregnancy and puberty) (19, 20) or pathophysiological [obesity (21) or insulin resistance (22)] states. Current literature suggests that various mechanisms exist for regulating and maintaining pancreatic β-cell mass (23, 24). Early studies utilizing [3H] thymidine incorporation experiments indicated that adult pancreatic endocrine cells belong to a class of tissues that could be maintained by the self-duplication of mature differentiated cells (25, 26). Recent immunohistochemical observations proposed that adult pancreatic stem or progenitor cells reside in the epithelium of pancreatic ducts (27, 28), within the islets (29, 30), or in the bone marrow (31) and contribute to the formation of new insulin-producing β-cells. Other studies suggest that acinar cells (32), non-insulin-producing islet cells (33), or splenocytes (34) can transdifferentiate into insulin-producing β-cells. β-cell expansion could also be promoted by epithelial-to-mesenchymal transition (EMT) or an EMT-like process (35). More recently, sophisticated direct lineage tracing performed on transgenic mice using the Cre/lox system demonstrated that adult pancreatic β-cells are formed by self-duplication of existing β-cells in the islets (36, 37) and that all β-cells contribute equally to islet growth and maintenance with no specialized progenitors (38, 39). In humans, the data on β-cell origin are scant, and the limited data suggest that a balance between both apoptosis and β-cell replication determines the overall adult β-cell mass (40). During the compensatory adaptive expansion in response to insulin resistance and hyperglycemia, β-cell mass can increase by cell size (hypertrophy), cell number (hyperplasia), and/or neogenesis together leading to enhanced insulin synthesis and secretion. However, a failure of the pancreatic islets to compensate because of one or more pathological causes leads to a series of events characterized by β-cell hypoplasia, apoptosis, and a relative increase in α-cells (41–43). Abnormal growth of islet cells can lead to the development of islet cell tumors that are generally named depending on the hormones they secrete. The most common islet cell tumor of the pancreas is the insulinoma (β-cell origin), of which up to 90% are benign. Diabetes mellitus is a risk factor for pancreatic cancer, although a small percentage of patients appear to have an inherited familial form of pancreatic cancer (44). Moreover, a recent study shows that patients with diabetes who reported smoking and were diagnosed 5 or more years before the study was conducted were associated with pancreatic cancer (45). However, despite several epidemiological and physiological studies, it is still unclear precisely where one disease stops and the other starts. Various nutrients and hormones have been implicated in regulating β-cell mass including glucose, insulin, insulin-like growth factors (IGFs), growth hormone (GH), glucagon-like peptide (GLP)-1, hepatocyte growth factor (HGF)/scatter factor, parathyroid hormone-related protein (PTHrP), and lactogens (reviewed in 46, 47). In addition to its role as a nutrient, glucose has been shown to increase β-cell mass in several models (48–52). GLP-1 controls blood glucose levels by stimulating insulin secretion, insulin biosynthesis, β-cell proliferation, and islet neogenesis and by inhibiting gastric emptying and glucagon release (53). The effects of GLP-1-induced proliferation of β-cells are non-additive with those of glucose, and the growth effects have been proposed to be mediated through different intermediates including phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (Akt), protein kinase C (PKC), and Jun. HGF and PTHrP are two potent β-cell mitogens, and recently, both have been shown to act through PKCζ(54). Among lactogens, prolactin (PRL) is a hormonal regulator of pregnancy, and β-cell replication induced through the PRL receptor is dependent on the Janus kinase/signal transduction and activators of transcription (JAK2/STAT5) signaling pathway. Moreover, PRL has been recently reported to repress menin levels and stimulate β-cell proliferation (55). Menin is a gene underlying the endocrine tumor syndrome termed multiple endocrine neoplasia type 1, which affects most notably the pancreas. In addition, intracellular Ca2+, a second messenger, has been reported to regulate nuclear factor of activated T cells and to integrate mitogenic signals from glucose, GLP-1, GH, and insulin to induce β-cell proliferation (47, 56). Insulin and IGF-I that mediate two ubiquitous signaling pathways will be discussed in more detail below. Leptin and adiponectin are two major adipokines that have been suggested to regulate compensatory β-cell growth in response to obesity (57). Leptin seems to have a dual role in β-cell growth because this adipokine has been demonstrated to lower phosphatase and TENsin homolog (PTEN) activity and promote p27 nuclear exclusion, which in turn promotes β-cell proliferation (58); however, leptin also mediates negative effects on insulin secretion by increasing phosphodiesterase 3B activity and decreasing cyclic adenosine monophosphate (cAMP) availability (59). Indeed, a mutation in the leptin receptor in the diabetic db/db mouse causes hyperinsulinemia and islet hyperplasia, but it was unclear whether the islet dysfunction is because of a lack of direct leptin action in β-cells or secondary to the effects of peripheral insulin resistance. Morioka et al. recently reported that mice lacking the leptin receptor specifically in the pancreas and fed normal chow manifested improved glucose tolerance, enhanced first-phase insulin response to glucose, and islet hyperplasia, implying a direct role for leptin action on the β-cells (60). Surprisingly, challenging these mice with a high-fat diet led to significantly greater glucose intolerance and poor compensatory islet growth. Together, these data provide genetic evidence for a critical role for leptin signaling in islet growth and function (60). Interactions between proteins in the leptin and insulin signaling pathways in the overall growth response during physiological (pregnancy) and pathological (obesity) states are worth exploring in the context of β-cell failure and development of T2D. Despite significant progress in identifying β-cell growth inducers and their signaling pathways, the cell cycle molecules responsible for tightly modulating β-cell proliferation during embryonic growth and underlying the compensatory growth response to insulin resistance have not been completely defined. Because β-cell replication is now accepted as essential for maintenance of adult β-cell mass (35, 36, 61–63), several investigators have focused on examining the proteins that are involved in the regulation of the G1/S transition in the β-cell cycle. Cell replication is generally modulated by the interaction of a diverse set of proteins that comprise the cyclins, the cyclin-dependent kinase (CDK), and the CDK inhibitor (CDKI) and requires a balance between the active complexes formed by cyclin–CDK and the CDKIs (reviewed in 47, 61). For example, cyclin D partners with CDK4 or CDK6 in early G1 and cyclin E partners with CDK2 in late G1, and both complexes phosphorylate the pRb (retinoblastoma protein) on different sites. This hyperphosphorylation of pRb leads to the release of E2F transcription factor (E2F) and the initiation of a transcriptional program required for entering the S phase of the cell cycle (64). There are two families of CDKIs: the inhibitor of CDK4 (INK) family composed of p15Inkb, p16Inka, p18Inkc, and p19Inkd and the CIP/KIP family including p21Cip1 and p27kip1. The INK proteins are specific inhibitors of CDK4 that partners cyclin D during the early G1 phase (65). The CIP/KIP proteins are inhibitors of CDK2, the partner of cyclin E in the late G1 phase, and they stabilize and enhance CDK4 function during cell cycle progression (65, 66). Although these cell cycle proteins are expressed in the islet (reviewed in 61, 67), only some of them have been directly implicated in β-cell proliferation (Fig. 1). Regulation of G1/S transition by growth factor (insulin and IGF-I) signaling in β-cells. Knockout mice (black square) or transgenic mice (gray circle) for some genes involved in this signaling pathway have been described to develop diabetes (see details and references in β-cell regeneration in diabetes mellitus). Akt, v-akt murine thymoma viral oncogene homolog; CDK4, cyclin-dependent kinase 4; c-myc, cellular myelocytomatosis oncogene; E2F 1/2, E2F transcription factor 1/2; FoxM1, forkhead box M1; FoxO-1, forkhead box O1; GSK3, glycogen synthase kinase 3; IGF, insulin-like growth factor; IGF-IR, insulin-like growth factor 1 receptor; IR, insulin receptor; IRS, insulin receptor substrate; MDM2, mouse double minute 2; Pdx1, pancreatic and duodenal homeobox 1; pRb, retinoblastoma 1; TGF-β, transforming growth factor beta; Smad, small mothers against decapentaplegic homolog. Cyclin D2, the most abundant cyclin in the islet, is critical for postnatal pancreatic β-cell growth (62, 68). Indeed, global knockout mice for cyclin D2 display decreased β-cell mass and glucose intolerance, leading to diabetes by 12 months of age (62), and the additional deletion of cyclin D1 in cyclin D2-deficient mice further decreases the β-cell mass (68). Interestingly, transgenic mice overexpressing cellular myelocytomatosis oncogene in β-cells, which has been shown to drive oncogenic cell proliferation through cyclin D (69), manifest β-cell proliferation and apoptosis, downregulation of insulin gene expression, and diabetes in early neonatal life (70). Mice with global knockouts for CDK4 develop β-cell hypoplasia and diabetes (71, 72), likely because of a lack of compensation secondary to the absence of CDK6 in β-cells. Conversely, mice transgenic for CDK4 manifest islet hyperplasia but do not develop hypoglycemia (71). Although mice deficient for E2F1 exhibit a defect in postnatal islet growth, reduced islet number and β-cell mass, and glucose intolerance, the mutants do not develop diabetes (73). Nevertheless, the additional deletion of E2F2 with E2F1 in these mice leads to insulin deficiency and pancreas dysplasia together leading to diabetes (74). Thus, the cyclin D/CDK4 complex and E2F family appear to have a crucial role in the regulation of β-cell mass, particularly in the β-cell compensatory response that is necessary to delay the onset of diabetes. pRb and p53 are central regulators of the cell cycle underlying G1/S arrest and are also tumor suppressors that have been reported to be frequently mutated in different forms of human cancer. Surprisingly, β-cell-specific deletion of pRb in mice does not lead to a severe phenotype, and the mutants only manifest limited effects on β-cell replication, mass, and function (75). Mice deficient for p53 are developmentally normal, and despite a susceptibility to develop spontaneous tumors (76), the mice do not develop insulinomas (77, 78), while mice lacking both pRb and p53 develop insulinomas and other islet tumors (77, 78). To our knowledge, no studies have been reported on islet and glucose metabolism in p53 global knockout mice. Among the proteins that comprise the CDKI families, an increased expression of p15Inkb in tumor necrosis factor-β transgenic mice was observed to correlate with pancreas hypoplasia, hypoinsulinemia, and diabetes in mice on both the non-obese diabetic and the B6 genetic backgrounds (79). Surprisingly, p21Cip1, a well-known target of p53, was recently reported not to be essential for maintaining β-cell mass or β-cell function in vivo, similar to the observations on pRb (80). While global knockout mice for p27kip1 exhibit no phenotype on postnatal β-cell expansion (81), β-cell-specific overexpression of p27kip1 leads to islet hypoplasia and diabetes (81). Moreover, an increase in nuclear localization of p27kip1 is observed in mice with pancreas-specific deletion of FoxM1 – a member of the forkhead box family (82). These mice show a decrease in β-cell mass and develop diabetes by 9 wk of age. Furthermore, double knockout for p27kip1 and p18Inkc display β-cell hyperplasia but fail to develop insulinomas (83, 84). The genetic studies described above support an important role for cell cycle inhibitors in β-cell growth. The relative levels of expression and activity of one or more of the cell cycle proteins lead either to diabetes in the case of cyclin D2, CDK4, E2F, or p27kip1 or to the development of cancer as discussed in the context of a combination of p53 with pRb or p27kip1 with p18Inkc. Further studies are necessary to directly delineate the role of p53 in both β- and α-cell pathophysiology. Because insulin resistance is an early predictor of T2D and IGF-I has been largely linked to cancer, the insulin/IGF-I system has been a popular area of investigation. Insulin and IGF-I constitute two primary members of the growth factor family, and their receptors are expressed ubiquitously and mediate the growth and metabolic effects of the hormones in virtually all tissues in mammals. Insulin and IGF-I classically bind to their own receptors but can also cross-react and activate common downstream proteins. Receptor activation transmits signals by phosphorylating insulin receptor substrates (IRSs) including the four IRS proteins, Shc, Gab-1, FAK, Cbl, or potentially other substrates, leading to a cascade activation mainly through PI3K/Akt to regulate multiple cellular processes such as glucose transport and utilization, protein synthesis, cell growth, proliferation, and antiapoptosis (reviewed in 85, 86) (Fig. 1). Mouse and human β-cells express both the insulin and the IGF-I receptors and most components in their signaling pathways (87–89). Interestingly, human α-, β-, and δ-cells have been reported to exhibit distinct expression patterns of proteins in the insulin signaling cascade (67, 90). Recent studies on the role of the insulin receptor (IR) signaling in β-cells have provided cumulative evidence for a role of autocrine action of insulin on its own receptor. Two early studies that provided direct genetic evidence for a role of insulin/IGF-I signaling in the regulation of β-cell biology include the β-cell-specific knockout of the insulin receptor (βIRKO) (91) and the global knockout of insulin receptor substrate-2 (IRS-2) (92). While the βIRKO mouse manifested a phenotype most resembling human T2D, mice with IRS-2KO failed to maintain their β-cell mass and developed diabetes. Following these two studies, multiple laboratories have reported the creation and characterization of transgenics and knockouts complemented by in vitro and ex vivo approaches to indicate the significance of proteins in the insulin/IGF-I cascade for the regulation of β-cells (91, 93–100). Several recent reviews provide an excellent resource for interested readers (85, 87, 101–103). While the potential of insulin and IGF-I as β-cell growth factors has been a topic of investigation for several years, we will focus largely on in vivo experiments that provide direct genetic evidence using homologous recombination to create mouse models to study phenotypes linked to β-cell biology. Global deletion of the insulin gene in mice leads to intra-uterine growth retardation and death because of ketoacidosis and hepatic steatosis (104). Interestingly, examination of pancreas during the postnatal period revealed islet hyperplasia because of an increase in islet cell proliferation and a reduction in apoptosis (105). Whereas global IGF-I knockout mice display growth retardation (106, 107), mice with a pancreas-specific knockout of the IGF-I gene manifest islet hyperplasia and are resistant to streptozotocin-induced diabetes (108). Transgenic mice expressing IGF-II, the other member of the IGF family that can activate both insulin and IGF-1 receptors in addition to its own IGF-II–mannose phosphate receptor, exhibit hyperplasic islets but surprisingly developed diabetes (109, 110). While the mechanisms underlying these defects are still unclear, one interpretation of these data is that insulin and IGF-I, contrary to the effects of IGF-II, are negative regulators of islet growth. Interestingly, mice expressing IGF-I in β-cells have been shown to regenerate pancreatic islets and counteract cytotoxicity and insulitis after treatment with multiple low doses of streptozotocin, suggesting that IGF-I gene transfer to the pancreas might be a suitable therapy for T1D (111, 112). Contrary to traditional thought and despite a role in β-cell proliferation, we and others have used genetic approaches to directly demonstrate that the insulin/IGF1 signaling pathway is not critical for early development of β-cells (91, 113–115). Indeed, although mice with a global knockout of IRs or IGF-I receptors die immediately after birth or manifest a variable survival rate in the case of IGF-1RKO, they are born with mature β-cells (116). Consistent with the observations that double or single knockout mice show unperturbed endocrine α- and β-cell development compared with control mice (116), β-cell-specific knockout mice for the insulin receptor (βIRKO) (91) or IGF-I receptor (βIGFRKO) (117, 118) are born with a normal complement of islet cells. However, although both βIRKO and βIGFRKO mice exhibit impaired glucose tolerance and reduced glucose-stimulated insulin secretion (GSIS), only βIRKO mice show an age-dependent decrease in β-cell mass and an increased susceptibility to develop overt diabetes (91, 97), suggesting a dominant role for insulin signaling in the regulation of adult β-cell mass (99). Mice lacking functional receptors for both insulin and IGF-1 only in β-cells were also born with a normal number of islet cells, but 3 wk after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants (99). Therefore, IR and insulin-like growth factor 1 receptor (IGF-IR) are not critical for development of β-cells, but a loss of action of these hormones in β-cells leads to diabetes. It has been observed for several decades that patients with T2D as well as mouse models of diabetes and obesity exhibit a remarkable ability to compensate for the increase in insulin demand in response to insulin resistance in liver, muscle, and adipose tissue (43, 119). One such model – the liver-specific IR knockout (LIRKO) mouse – develops severe insulin resistance and glucose intolerance, but mice do not become overtly diabetic due, in part, to a ∼30-fold increase in β-cell mass (120). Furthermore, the enhanced β-cell proliferation shows a striking and persistent positive correlation with high circulating insulin levels in contrast to blood glucose levels that decrease in aging LIRKO mice (121). It is possible that insulin-resistant hepatocytes in these mice transmit signals to the endocrine pancreas through circulating growth factors that promote β-cell compensation. Consistent with a role for insulin signaling in β-cell proliferation, compound LIRKO/βIRKO mice fail to develop compensatory islet hyperplasia in response to insulin resistance (121). Besides, insulin itself is an obvious candidate for β-cell proliferation considering that insulin levels are elevated because of insulin resistance. Indeed, a recent in vitro study shows that insulin, at levels that have been measured in vivo, can directly stimulate β-cell proliferation (122). IRSs and Akt, important downstream signaling molecules in the IR/IGF-IR signaling pathway, have been reported to play a dominant role in β-cell growth. Indeed, global knockout of IRS-1 in mice leads to postnatal growth retardation and hyperplasic and dysfunctional islets. However, the mice do not develop overt diabetes because of β-cell compensation (94, 95, 123, 124). In contrast, IRS-2 global knockouts develop only mild growth retardation and, depending on their genetic background, develop either mild glucose intolerance (92, 125) or β-cell hypoplasia and overt diabetes (92). β-cell-specific deletion of IRS-2 (βIRS2KO) also leads to mild diabetes (126–128). To avoid potential extrapancreatic effects of the RIP-Cre promoter used to create the βIRS2KO mice, knockouts have also been generated using a Cre recombinase driven by the PDX-1 promoter (129). βIRS2KO mice exhibit reduced β- and α-cell mass and impaired glucose homeostasis (129). Thus, IRS-2 appears to be a positive regulator of β-cell mass and β-cell compensation, while IRS-1 predominantly regulates insulin secretion. A similar scenario is observed in the context of the Akt isoforms. Thus, global knockouts for Akt2 develop overt diabetes largely because of insulin resistance in peripheral tissues and β-cell failure, despite islet hyperplasia and hyperinsulinemia (130, 131). Transgenic mice expressing a kinase-dead mutant of Akt1 showed increased susceptibility to develop glucose intolerance and diabetes following fat feeding (132). Islet hyperplasia, β-cell hypertrophy, and hyperinsulinemia are observed in β-cell-specific transgenic mice expressing constitutively active Akt1. However, these mice show improved glucose tolerance and a resistance to experimental diabetes (133, 134). These in vivo data are supported by a recent in vitro study in other cell types (myoblasts and fibroblasts) that Akt1 is necessary for proliferation, while Akt2 promotes cell cycle exit and support a dual role for the Akts in the regulation of β-cell mass (135). Moreover, mutation in the human Akt2 gene has been described in a family with severe insulin resistance and diabetes, indicating a role for Akt signaling in maintaining tissue insulin sensitivity in humans (136). The role of PI3K – a critical node between the IRS and the Akt – has also been examined in the context of islet biology, although its role is not fully understood (86). PI3K appears to play a role in the differentiation of acinar cells following pancreas resection (137) and pancreatic duct cell differentiation into insulin-producing cells, in part, by regulating PDX-1 (138). These results are based on experiments aimed at inhibiting PI3K chemically using wortmannin or small interfering RNA against the p85α subunit of PI3K (138). Multiple roles of the PI3K/Akt pathway have been described not only in cell cycle progression, which are notably linked to tumor-promoting effect of this pathway (reviewed in 139), but also in physiological β-cell proliferation. Considering the above reports on IRS and Akt isoforms, it is likely that Akt1 mediates its proliferative effect following activation of IRS-2, whereas Akt2 is associated with antiproliferative effects following IRS-1 stimulation. A recent review provides a discussion of the role of Akt in the regulation of β-cell proliferation (reviewed in 140). One of the downstream molecules of Akt known to be involved in proliferation is glycogen synthase kinase 3 (GSK3). Akt mediates phosphorylation and inactivation of GSK3 upon stimulation (141) (Fig. 1). While no such direct evidence has been demonstrated in β-cells, GSK3 phosphorylation was observed in mice overexpressing a constitutively active form of Akt1, which correlated with an increase in cyclin D1 levels in islet lysates (142). These data suggest a role for GSK3 inhibition in β-cell cycle progression because GSK3 has been shown in other cell types to phosphorylate and promote degradation of cyclin D1 (143, 144). More recently, Huang et al. have shown that the GSK3β/β-catenin/T cell specific factor (TCF) pathway in cooperation with cAMP response element binding protein (CREB) can downregulate the cyclin D2 expression by PTEN, suggesting a convergence of the PI3K/PTEN and the Wnt pathways in the modulation of cyclin D2 expression (145). Recent experiments have also linked the cyclin/CDK4 complex to Akt in β-cell proliferation, showing that Akt1 upregulates cyclin D1, cyclin D2, and p21Cip1 levels (but not p27Kip1) and CDK4 activity (142). Moreover, this study shows that CDK4 is indispensable for β-cell proliferation induced by Akt1 in these transgenic mice. While only Akt1 appears to be required for proliferation, Akt2 has been shown in myoblast to promote cell cycle exit through specific p21Cip1 binding (135). Indeed, Heron-Milhavet et al. have demonstrated in vitro that silencing Akt1 resulted in decreased cyclin A levels and inhibition of S phase entry, whereas no effects were observed with Akt2 knockdown except for reduced p21Cip1 levels. In contrast, overexpression of Akt2 reduced cyclin A expression and delayed cell cycle progression with increased nuclear expression of p21Cip1. Thus, the cyclin D/CDK4 complex is a likely target or mediator of PI3K/Akt pathways in the islet (Fig. 1). The FoxO proteins are other important downstream targets of Akt that are known to regulate the β-cell cycle (reviewed in 146, 147). Phosphorylation by Akt regulates the subcellular localization of FoxO proteins, translocating them from the nucleus to the cytoplasm where they are inactive and ubiquinated. Akt therefore negatively regulates the transcriptional activity of FoxO proteins. Transcriptional repression of cyclin D has been shown to be required for FoxO-mediated inhibition of cell cycle progression and transformation (148). Moreover, FoxO proteins have been reported to upregulate the transcription of p27Kip1 (149). Nevertheless, p27Kip1 does not seem to be a main factor regulated by Akt for β-cell progression (142). Thus, one downstream mechanism that has been proposed for β-cell proliferation by FoxO is the regulation of Pdx1 expression (150). Indeed, the phosphorylation of FoxO1 by Akt is believed to prevent the transcription factor Fo" @default.
• W2034451334 created "2016-06-24" @default.
• W2034451334 creator A5042315373 @default.
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• W2034451334 date "2009-02-01" @default.
• W2034451334 modified "2023-10-07" @default.
• W2034451334 title "Growth factor control of pancreatic islet regeneration and function" @default.
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