Hamartin and Tuberin Expression in Human Tissues

Johnson, Michael W.; Kerfoot, Christopher A.; Bushnell, Theodore; Li, Marissa; Vinters, Harry V.

doi:10.1038/modpathol.3880286

Cited by 57 publications

(37 citation statements)

References 26 publications

(28 reference statements)

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“…This association has been demonstrated by immunohistochemical colocalization studies (58)(59)(60)(61)(62)(63) as well as by coimmunoprecipitation from subcellular fractions (64). In their elegant series of experiments, Nellist and colleagues (44) showed that hamartin and tuberin are binding partners that coelute from subcellular fractions in a complex with a molecular weight of 450 kD, larger than the combined molecular weights of hamartin and tuberin.…”

Section: Hamartin and Tuberin Physically Interactmentioning

confidence: 99%

Molecular Pathogenesis of Lymphangioleiomyomatosis

Juvet

McCormack²,

Kwiatkowski³

et al. 2007

Am J Respir Cell Mol Biol

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Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease affecting young women. The pivotal observation that LAM occurs both spontaneously and as part of the tuberous sclerosis complex (TSC) led to the hypothesis that these disorders share common genetic and pathogenetic mechanisms. In this review we describe the evolution of our understanding of the molecular and cellular basis of LAM and TSC, beginning with the discovery of the TSC1 and TSC2 genes and the demonstration of their involvement in sporadic (non-TSC) LAM. This was followed by rapid delineation of the signaling pathways in Drosophila melanogaster with confirmation in mice and humans. This knowledge served as the foundation for novel therapeutic approaches that are currently being used in human clinical trials.Keywords: tuberous sclerosis; TSC1; TSC2; mTOR; signal transduction; estrogen Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease of uncertain etiology that affects young women. LAM cysts are formed as a result of the proliferation of an abnormal smooth muscle-like cell, the LAM cell. The mechanism by which LAM cells cause this architectural distortion of the lung is unknown. The clinical course of LAM is frequently inexorable, leading to death or lung transplantation in 10 to 15 years, although recent studies indicate that there is much variability in the natural history of the disorder (1, 2). The most common clinical manifestation is the insidious onset of exertional dyspnea; patients may also experience a nonproductive cough. Other common features include spontaneous pneumothorax, which results from cyst rupture, and chylothorax, which results from obstruction of pulmonary lymphatics and hilar lymph nodes by the slowly proliferating LAM cells. Less frequently, hemoptysis or chyloptysis may occur (1, 2).Most of the current therapies for LAM are supportive in nature. Bronchodilators are offered because many patients have obstructive physiology, often with some degree of reversibility, on pulmonary function testing. Oxygen is provided to patients with significant hypoxia. Current recommendations stipulate

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Section: Hamartin and Tuberin Physically Interactmentioning

confidence: 99%

Molecular Pathogenesis of Lymphangioleiomyomatosis

Juvet

McCormack²,

Kwiatkowski³

et al. 2007

Am J Respir Cell Mol Biol

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“…2). 14,15 Most reports localise hamartin in the cytoplasm, although 1 of the studies explaining lack of TSC1/TSC2 complex activity in spite of the presence of wild-type proteins demonstrated nuclear localisation. 16 The protein is hydrophilic and has a single transmembrane domain at amino acids 127-144 and a predicted coiled-coil region at residues 719-998.…”

Section: Hamartinmentioning

confidence: 99%

Hamartin and tuberin: Working together for tumour suppression

Jóźwiak

2005

Intl Journal of Cancer

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TSC1 and TSC2 are two recently identified tumour suppressor genes encoding hamartin and tuberin, respectively, and involved in pathogenesis of tuberous sclerosis, neurological disorder connected with the development of hamartomas in numerous organ systems, including the brain, kidneys, heart and liver. Both protein products of TSC1 and TSC2 form an intracellular complex exerting GTPase-activating (GAP) activity towards a small G protein, Ras homologue enriched in brain (Rheb). Inhibition of Rheb is important for the regulation of mTOR pathway, while mutation of hamartin or tuberin results in uncontrolled cell cycle progression. Tuberin, possessing the Rheb-GAP domain, is phosphorylated by several kinases that confer the signals of growth factor stimulation or low cellular energy levels. Such a modification of tuberin influences its activity within the complex with hamartin and positively or negatively modulates mTOR-regulated protein translation and cellular proliferation. Current article describes biochemical properties of hamartin and tuberin, their known regulatory phosphorylation sites and binding partners. ' 2005 Wiley-Liss, Inc.

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“…Most 'second hits' are large deletions involving loss of surrounding loci and loss of heterozygosity (LOH) in TSC1 or TSC2, which have (Sancak et al 2005). However, the most common TSC-associated lesions are limited to relatively few organs including the brain, heart, kidney, lungs and skin, while the TSC gene products (hamartin and tuberin) are expressed in most tissues (Johnson et al 2001). Tuberin was present in abundance in control brains, but was lost from TSC tissues, such as cerebral cortices, cortical tubers and subependymal giant-cell astrocytomas (Mizuguchi et al 1996).…”

Section: Molecular Biology Of Tscmentioning

confidence: 99%

Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review

Dworakowska¹,

Grossman²

2009

Endocrine-Related Cancer

107

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Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterised by the development of multiple hamartomas in numerous organs. It is caused by mutations of two tumour suppressor genes, TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3, which encode for hamartin and tuberin respectively. The interaction between these two proteins, the tuberin-hamartin complex, has been shown to be critical to multiple intracellular signalling pathways, especially those controlling cell growth and proliferation. TSC may affect skin, central nervous system, kidneys, heart, eyes, blood vessels, lung, bone and gastrointestinal tract. Small series and case reports have documented that in tuberous sclerosis patients many endocrine system alterations might occur, affecting the function of the pituitary, parathyroid and other neuroendocrine tissue. There have been scattered reports of the involvement of such tissue in the pathological process of TSC, but no systematic review as to whether this is a true association. We have therefore systematically assessed all available published literature in this area. We conclude that there may be an association with pituitary and parathyroid tumours, and two recent descriptions of Cushing's disease are especially intriguing. However, the evidence seems more firm in the case of islet cell tumours, particularly insulinomas. As these latter may cause changes in mental state that may be confused with the cerebral manifestations of TSC per se, it is particularly important for physicians working with these patients to be aware of the putative and indeed likely association.

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Hamartin and Tuberin Expression in Human Tissues

Cited by 57 publications

References 26 publications

Molecular Pathogenesis of Lymphangioleiomyomatosis

Molecular Pathogenesis of Lymphangioleiomyomatosis

Hamartin and tuberin: Working together for tumour suppression

Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review

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