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Tsc and primary cilia

Rinzhin T Sherpa, Kimberly F Atkinson, Viviana P Ferreira, Surya M Nauli
Primary cilia arebiophysically-sensitive organelles responsible for sensing fluid-flow and transducing this stimulus into intracellular responses. Previous studies have shown that the primary cilia mediate flow-induced calcium influx, and sensitivity of cilia function to flow is correlated to cilia length. Cells with abnormal cilia length or function can lead to a host of diseases that are collectively termed as ciliopathies. Rapamycin, a potent inhibitor of mTOR (mammalian target of rapamycin), has been demonstrated to be a potential pharmacological agent against the aberrant mTOR signaling seen in ciliopathies such as polycystic kidney disease (PKD) and tuberous sclerosis complex (TSC)...
December 2016: International Education and Research Journal
Tamina Seeger-Nukpezah, Joy L Little, Victoria Serzhanova, Erica A Golemis
The primary cilium is a well-established target in the pathogenesis of numerous developmental and chronic disorders, and more recently is attracting interest as a structure relevant to cancer. Here we discuss mechanisms by which changes in cilia can contribute to the formation and growth of tumors. We emphasize the cancer-relevance of cilia-dependent signaling pathways and proteins including mTOR, VHL, TSC, WNT, Aurora-A, NEDD9, and Hedgehog, and highlight the emerging role of ciliary dysfunction in renal cell carcinoma, medulloblastoma, and breast cancer...
December 1, 2013: Drug Discovery Today. Disease Mechanisms
Moe R Mahjoub, Tim Stearns
The primary cilium is a nexus of cell signaling, and ciliary dysfunction is associated with polycystic kidney disease, retinal degeneration, polydactyly, neural tube defects, and obesity (ciliopathies). Signaling molecules for cilium-associated pathways are concentrated in the cilium, and this is essential for efficient signaling. Cilia are nucleated from centrioles, and aberrant centriole numbers are seen in many cancers and in some ciliopathies. We tested the effect of supernumerary centrioles on cilium function and found that cells with extra centrioles often formed more than one cilium, had reduced ciliary concentration of Smoothened in response to Sonic hedgehog stimulation, and reduced Shh pathway transcriptional activation...
September 11, 2012: Current Biology: CB
Eric A Armour, Robert P Carson, Kevin C Ess
Tuberous sclerosis complex (TSC) is a multiorgan hamartomatous disease caused by loss of function mutations of either the TSC1 or TSC2 genes. Neurological symptoms of TSC predominate in younger patients, but renal pathologies are a serious aspect of the disease in older children and adults. To study TSC pathogenesis in the kidney, we inactivated the mouse Tsc1 gene in the distal convoluted tubules (DCT). At young ages, Tsc1 conditional knockout (CKO) mice have enlarged kidneys and mild cystogenesis with increased mammalian target of rapamycin complex (mTORC)1 but decreased mTORC2 signaling...
August 15, 2012: American Journal of Physiology. Renal Physiology
Tobias B Huber, Gerd Walz, E Wolfgang Kuehn
The immunosuppressive drug rapamycin has helped to identify a large signaling network around the target of rapamycin (TOR) protein that integrates information on nutrient availability and growth factors to control protein synthesis and cell size. Studies using rapamycin in animal models of kidney disease indicate that mTOR deregulation has a role in glomerular disease, polycystic kidney disease, and renal cancer. The role of mTOR activation in podocytes is context dependent, and indirect evidence suggests that mTOR may have a role in chronic podocyte loss...
March 2011: Kidney International
Venkata S Katabathina, Gopi Kota, Anil K Dasyam, Alampady K P Shanbhogue, Srinivasa R Prasad
Renal cystic diseases in adults are a heterogeneous group of disorders characterized by the presence of multiple cysts in the kidneys. These diseases may be categorized as hereditary, acquired, or developmental on the basis of their pathogenesis. Hereditary conditions include autosomal dominant polycystic kidney disease, medullary cystic kidney disease, von Hippel-Lindau disease, and tuberous sclerosis. Acquired conditions include cystic kidney disease, which develops in patients with end-stage renal disease...
October 2010: Radiographics: a Review Publication of the Radiological Society of North America, Inc
Ruhee Dere, Patricia D Wilson, Richard N Sandford, Cheryl Lyn Walker
Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited renal disorder caused by defects in the PKD1 or PKD2 genes. ADPKD is associated with significant morbidity, and is a major underlying cause of end-stage renal failure (ESRF). Commonly, treatment options are limited to the management of hypertension, cardiovascular risk factors, dialysis, and transplantation when ESRF develops, although several new pharmacotherapies, including rapamycin, have shown early promise in animal and human studies...
February 16, 2010: PloS One
Cleo S Bonnet, Mark Aldred, Christopher von Ruhland, Rebecca Harris, Richard Sandford, Jeremy P Cheadle
Clinical trials are underway for the treatment of tuberous sclerosis (TSC)-associated tumours using mTOR inhibitors. Here, we show that many of the earliest renal lesions from Tsc1+/- and Tsc2+/- mice do not exhibit mTOR activation, suggesting that pharmacological targeting of an alternative pathway may be necessary to prevent tumour formation. Patients with TSC often develop renal cysts and those with inherited co-deletions of the autosomal dominant polycystic kidney disease (ADPKD) 1 gene (PKD1) develop severe, early onset, polycystic kidneys...
June 15, 2009: Human Molecular Genetics
Tiffiney R Hartman, Dongyan Liu, Jack T Zilfou, Victoria Robb, Tasha Morrison, Terry Watnick, Elizabeth P Henske
Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome in which severe renal cystic disease can occur. Many renal cystic diseases, including autosomal dominant polycystic kidney disease (ADPKD), are associated with absence or dysfunction of the primary cilium. We report here that hamartin (TSC1) localizes to the basal body of the primary cilium, and that Tsc1(-/-) and Tsc2(-/-) mouse embryonic fibroblasts (MEFs) are significantly more likely to contain a primary cilium than wild-type controls...
January 1, 2009: Human Molecular Genetics
A Sessa, M Righetti, G Battini
It is possible to identify renal cysts in several subjects by ultrasonography imaging techniques. Among the inherited polycystic kidney diseases we include autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic diseases such as von Hippel-Lindau disease, tuberous sclerosis complex (TSC1 and TSC2), and autosomal dominant polycystic kidney disease (ADPKD). ARPKD is a rare disease, related to PKHD1 gene, located on chromosome 6p21, that encodes a protein named polyductin/fibrocystin...
December 2004: Minerva Urologica e Nefrologica, the Italian Journal of Urology and Nephrology
P P Liberski, R Kordek
The ultrastructural pathology of primary brain tumors of glial origin is examined. These are divided into two major groups. The first category comprises astrocytoma with the variants: fibrillary, protoplasmic, gemistocytic, and anaplastic. These are biologically aggressive tumors of a relatively high proliferative potential and include a substantial proportion of cases that transform into the most malignant secondary glioblastoma. The second category, comprised of rather benign tumors of a limited proliferative capacity and a reasonable good prognosis, includes such clinico-pathological entities as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and subependymal giant cell astrocytoma of tuberous sclerosis...
January 1997: Ultrastructural Pathology
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