Tuberous Sclerosis in a 19-Week Fetus: Immunohistochemical and Molecular Study of Hamartin and Tuberin

Wei, Jian‐Jun; Chiriboga, Luis; Mizuguchi, Masashi; Yee, Herman; Miller, Douglas C.; Greco, M. Alba

doi:10.1007/s10024-001-0210-3

Cited by 27 publications

(21 citation statements)

References 47 publications

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“…This is supported by subcellular localization studies of tuberin-hamartin complexes in human fetuses and tissues (12), biochemical fractionation studies (13)(14)(15), and functional studies on tuberin and hamartinassociated signaling pathways (15,16). Our previously published data provide evidence for the direct involvement of tuberin in nuclear events and, more specifically, in estrogen genomic signaling; here too, the preponderance of evidence suggests that this activity is in the absence of any hamartin interactions (10,15,17).…”

Section: Introductionmentioning

confidence: 53%

Tuberin Nuclear Localization Can Be Regulated by Phosphorylation of Its Carboxyl Terminus

York

Lou

2006

Molecular Cancer Research

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Tuberin, the tuberous sclerosis 2 (TSC2) gene product, has been identified as a tumor suppressor protein genetically implicated in the pathology of tuberous sclerosis and the female-specific lung disease lymphangioleiomyomatosis. Tuberin and its predominant cytoplasmic binding partner hamartin have been shown to complex with a variety of intracellular signaling regulators and affect the processes of protein translation, cellular proliferation, cellular migration, and cellular transcription. In previous studies, we have presented evidence for tuberin binding to the calcium-dependent intracellular signaling protein calmodulin (CaM), overlap of tuberin CaM binding domain with a binding domain for estrogen receptor A, and the phosphorylation-associated nuclear localization of tuberin. In the study presented here, we expand our findings on the mechanism of tuberin nuclear localization to show that the CaM-estrogen receptor-A binding domain of tuberin can also serve as a tuberin nuclear localization sequence. Furthermore, we identify an Akt/p90 ribosomal S6 kinase-1 phosphorylation site within the carboxyl terminus of tuberin that can regulate tuberin nuclear localization and significantly affect the ability of tuberin to modulate estrogen genomic signaling events. These findings suggest a link between tuberin nuclear localization and a variety of intracellular signaling events that have direct implications with respect to the role of tuberin in the pathology of tuberous sclerosis and lymphangioleiomyomatosis. (Mol Cancer Res 2006;4(11):885 -97)

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Section: Introductionmentioning

confidence: 53%

Tuberin Nuclear Localization Can Be Regulated by Phosphorylation of Its Carboxyl Terminus

York

Lou

2006

Molecular Cancer Research

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“…15 They normally inhibit cell proliferation by a negative regulation of the cell cycle and in part through the insulin receptor signal pathway. 16,17 Inactivation of either tuberous sclerosis gene 2 or tuberous sclerosis gene 1 genes leads to the formation of mostly benign neoplasms in patients with tuberous sclerosis complex.…”

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confidence: 99%

Expression profile of tuberin and some potential tumorigenic factors in 60 patients with uterine leiomyomata

et al. 2005

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Human uterine leiomyomata are the most common tumors in women of reproductive age. The pathogenesis of leiomyomata remains unknown. An animal model of Eker rats with deleted tuberous sclerosis complex gene 2 (tuberin) shows increased incidence of leiomyomata. The role of tuberin in human leiomyomata is unknown. In this study, we designed a tissue microarray with tissue cores of leiomyomata and the matched myometrium from 60 hysterectomy specimens. We examined the expression of tuberin and tuberous sclerosis complex gene 1 product hamartin, proteins of the insulin-signaling pathway, steroid receptors and some of their cofactors, and human mobility group gene A2 by immunohistochemistry. We found that nearly half of the cases displayed either reduction or loss of tuberin in leiomyomata compared with matched normal myometrium. No change of hamartin was noted. Furthermore, a significant reduction of glucocorticoid receptor was found in leiomyomata with reduced tuberin. The proteins insulin like growth factor 1, insulin-like growth factor receptor b, AKT kinase, and phosphatidylinositol 3-kinase were upregulated. Nearly half of leiomyomata show upregulation of human mobility group gene A2, along with the steroid receptor cofactors. Our findings suggest that there are two broad groups of uterine leiomyomata. One group is associated with an alteration of tuberin and glucocorticoid receptor. The other group is associated with upregulation of human mobility group gene A2 and steroid receptor cofactors.

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“…Experiments in Drosophila (44, 45) demonstrated that the presence of both proteins in cells was necessary in controlling tissue mass. Our data (35) suggest that loss of either protein from tissues in which normally both are present is associated with a high incidence of hamartoma formation in early childhood. Therefore, interruption of the protein-protein interaction between hamartin and tuberin, such as altered localization of one of the proteins, may interrupt their normal function.…”

Section: Discussionmentioning

confidence: 52%

“…Hamartin and tuberin may function in different cellular locations. In our previous study with pediatric tissues, we found that hamartin and tuberin were indeed expressed in different subcellular regions in different tissues or cells (35). The significance of the different cellular localization of hamartin and tuberin is not known.…”

Section: Discussionmentioning

confidence: 90%

“…The association between hamartin and ␤-catenin in the regulation of cellcell adhesion is not known. Because hamartin, tuberin, GCR, and p27 are expressed in normal gastric mucosa (32)(33)(34)(35), the expression pattern of these proteins in sporadic FGPs is of interest, although no typical FGPs are reported in TSC. The aim of this study is to investigate the localization of hamartin, tuberin, GCR, and p27 in sporadic FGPs, using normal fundic mucosa for comparison.…”

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confidence: 99%

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Altered Cellular Distribution of Tuberin and Glucocorticoid Receptor in Sporadic Fundic Gland Polyps

et al. 2002

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Gastric fundic gland polyps (FGPs) are considered hamartomas, and various gastrointestinal hamartomas are associated with tuberous sclerosis complex (TSC). The aim of this study was to investigate a possible link between TSC proteins (hamartin and tuberin) and sporadic FGPs. We examined 33 sporadic FGPs and 26 biopsies of normal fundic mucosa by immunohistochemistry. Nuclear immunoreactivity for tuberin was dramatically reduced or lost in most sporadic FGPs, and tuberin unexpectedly accumulated in the cytoplasm in oxyntic glands. About 18% (6/33) of FGPs were immunopositive in an average of 1.7% of oxyntic cell nuclei, compared with 77% (20/26) of controls in an average of 24.4% of oxyntic cell nuclei (P < .01). No change in hamartin was noted. We further examined the tuberin-associated proteins glucocorticoid receptor (GCR) and p27. Nuclear immunoreactivity for GCR was lost in most sporadic FGPs, but p27 distribution was normal. Sporadic FGPs had a low frequency of staining for Ki-67 except for some cells from cystic components, which is consistent with their slow growth. Our results are consistent with the hypothesis that tuberin may play an important role in pathogenesis of sporadic FGPs. First, an altered cellular localization of tuberin may lead to the deregulation of cell proliferation by interrupting its interaction with hamartin. Second, altered cellular localization of tuberin may preclude its negative regulation of gene transcription mediated by GCR.

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Tuberous Sclerosis in a 19-Week Fetus: Immunohistochemical and Molecular Study of Hamartin and Tuberin

Cited by 27 publications

References 47 publications

Tuberin Nuclear Localization Can Be Regulated by Phosphorylation of Its Carboxyl Terminus

Tuberin Nuclear Localization Can Be Regulated by Phosphorylation of Its Carboxyl Terminus

Expression profile of tuberin and some potential tumorigenic factors in 60 patients with uterine leiomyomata

Altered Cellular Distribution of Tuberin and Glucocorticoid Receptor in Sporadic Fundic Gland Polyps

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