The authors had total responsibility for the content and writing of the manuscript. and peritubular capillary loss, vasospasm, and hypertension. They impair podocyte integrity pathways and may predispose to glomerular injury. Administration Closantel of mTOR inhibitors is discontinued because of side effects in up to 40% of transplant recipients. Currently, treatment with mTOR inhibitors should not be recommended to treat ADPKD. Results of ongoing studies must be awaited and patients informed accordingly. If effective, lower dosages than those used to prevent rejection would minimize side effects. Combination therapy with other effective drugs could improve tolerability and results. Careful clinical observations have been key to the identification of the genes mutated in autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis complex (TSC), the function of the gene products, and mammalian target of rapamycin (mTOR) signaling as an important player in the pathogenesis of ADPKD and hamartomatous diseases. ADPKD, a potentially lethal monogenic disorder with an estimated prevalence of 1 1:400 to 1 1:1000, is characterized by the development of cysts in the kidneys, liver, seminal vesicles, pancreas, and arachnoid membrane; intracranial aneurysms and dolichoectasias; aortic root dilation and aneurysms; mitral valve prolapse; and abdominal wall hernias (1). TSC, an autosomal dominant disease with a prevalence of 1 1:6000 to 1 1:10,000, is characterized by multiple brain, retina, skin, kidney, heart, and lung hamartomas (2). A Portuguese family segregating a chromosome 16:22 translocation with ADPKD and TSC helped to identify the and genes immediately adjacent to each other on chromosome 16 (3,4). The cloning of and subsequently and and homologues in and the subsequent identification of the hamartin-tuberin heterodimer as a GTPase-activating protein for Rheb (Ras homolog enriched in brain), linking growth factor, nutrient, and energy sensing signals to mTOR and mTOR-dependent targets (6). The description of a contiguous gene syndrome characterized by early onset of severe polycystic kidney disease (PKD) in patients with deletions involving and suggested that Closantel polycystin-1 and tuberin function in a common pathway (7). A better understanding of Closantel the molecular mechanisms Closantel laid out the foundation for the development of potentially effective therapies (8). The purpose of this review is to critically analyze the potential benefits and risks of mTOR inhibitors to treat ADPKD, TSC, and other hamartomatous diseases. Overview of mTOR Signaling and Inhibitors mTOR is a serine/threonine kinase of the phosphoinositide 3-kinase (PI3K)-related kinase family identified as the mammalian target of rapamycin (sirolimus). Rapamycin is a fungal metabolite found to have potent growth-inhibitory and immunosuppressant properties (9,10). mTOR is the core component of two distinct complexes only partially characterized: complex 1 (mTORC1) and complex 2 (mTORC2) (9). In addition to mTOR, Closantel both complexes contain the small adaptor G(16), whereas the GTPase-activating protein (GAP) inducing its inactive state is tuberin, the gene product (17). The mechanisms regulating the complex have been the focus of intense investigations, leading to the identification of several cascades that regulate the GAP activity of (23), and the hypoxia-induced molecule REDD1 (24). Open in a separate window Figure 2 Overview of the cascades converging on regulation of the TSC2 gene product tuberin. Downstream of the Mouse monoclonal to CK16. Keratin 16 is expressed in keratinocytes, which are undergoing rapid turnover in the suprabasal region ,also known as hyperproliferationrelated keratins). Keratin 16 is absent in normal breast tissue and in noninvasive breast carcinomas. Only 10% of the invasive breast carcinomas show diffuse or focal positivity. Reportedly, a relatively high concordance was found between the carcinomas immunostaining with the basal cell and the hyperproliferationrelated keratins, but not between these markers and the proliferation marker Ki67. This supports the conclusion that basal cells in breast cancer may show extensive proliferation, and that absence of Ki67 staining does not mean that ,tumor) cells are not proliferating. tyrosine kinase receptor (TKR) signaling, Akt, ERK, and p90RSK can all phosphorylate different residues of TSC2, resulting in inhibition of its GAP activity toward Rheb (right diagram). As a result, activation of TKRs results in activation of the mTORC1 cascade. Amino acids can also activate mTORC1 downstream of the TSC1/TSC2 complex by acting directly on mTORC1. In contrast, REDD1, AMPK, and GSK3act as energy or hypoxia sensors and.