G-Proteins: implications for pathophysiology and disease

Gordeladze, Jan O.; Johansen, Per Wiik; Paulssen, Ruth H.; Paulssen, Eyvind J.; Gautvik, Kaare M.

doi:10.1530/eje.0.1310557

Cited by 24 publications

(8 citation statements)

References 60 publications

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“…The skeletal abnormalities which we have identified in RS are similar to those found in Albright's Hereditary Osteodystrophy (Leonard et al 1995) which is associated with endocrine disturbances and a mutation in the alpha subunit of a stimulatory G protein (Patten et al 1990). G proteins also play a role in the growth and differentiation of osteoblasts (Gordeladze et al 1994). Screening of girls with RS for biochemical and/or functional abnormalities of G proteins could be important if our findings of reduced bone mass were to have a metabolic basis.…”

Section: Discussionmentioning

confidence: 99%

A population‐based approach to the investigation of osteopenia in Rett syndrome

Leonard

Thomson

Glasson

et al. 1999

Develop Med Child Neuro

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This study compares bone mass in a national sample of girls with Rett syndrome (RS) with a sample of control children. The Australian RS Database was the source of cases for this population‐based study. Hand radiographs were available from 101 of 137 subjects (74% of the known Australian population of girls with RS aged ? 20 years). Control radiographs matched for age, sex, and laterality were obtained from hospital radiology departments. A measure of cortical thickness was made from the difference between the outer diameter and the medullary space in the second metacarpal bone. A mean z ‐score value for cortical thickness and percentage cortical area for each individual was calculated. The mean cortical thickness (z score) for girls with RS was –1.94 compared with –0.38 for control children (P<0.001). In girls with RS, the mean cortical thickness decreased with age (P<0.001). In girls who were taking epilepsy medication it was –2.21 compared with –1.23 in those not taking epilepsy medication (P<0.001). There was no evidence of a beneficial effect of increased calcium intake on cortical thickness. A similar pattern was obtained when percentage cortical area was estimated. In multivariate analysis, increasing age and use of anticonvulsant medication were associated with decreased cortical thickness and only use of anticonvulsant medication with decreased percentage cortical area. Fractures had occurred in one‐third of cases and it was estimated that just over 40% of girls would sustain a fracture by the age of 15 years. Girls with RS may be at increased risk of fractures and their bone quality compromised as determined by cortical thickness and percentage cortical area measurements from the second metacarpal.

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Section: Discussionmentioning

confidence: 99%

A population‐based approach to the investigation of osteopenia in Rett syndrome

Leonard

Thomson

Glasson

et al. 1999

Develop Med Child Neuro

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“…As previously demonstrated for nuclear hormone receptors and growth factor receptors, it has been proposed that components of G protein signaling pathways may potentially be involved in the development of neoplastic and non-neoplastic human diseases (1±6, 22,23). In fact, it has been demonstrated that mutations in the genes encoding these proteins are responsible for several human diseases presenting with the clinical phenotype of hormone excess or defect.…”

Section: Abnormalities Of G Protein Signaling Pathwaysmentioning

confidence: 97%

“…Due to the ubiquitous expression of Gsa, late occurring mutations cause focal disease such as acromegaly and toxic thyroid adenomas, while when the same mutations occur very early in embryogenesis they cause disorders with widespread manifestations, such as McCune±Albright syndrome (MAS). It is tempting to speculate that activating germ-line mutations of Gsa would be incompatible with life (23).…”

Section: Gsp Oncogene In Mccune±albright Syndromementioning

confidence: 99%

G protein mutations in endocrine diseases

Lania

Mantovani

Spada

2001

European Journal of Endocrinology

100

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This review summarizes the pathogenetic role of naturally occurring mutations of G protein genes in endocrine diseases. Although in vitro mutagenesis and transfection assays indicate that several G proteins have mitogenic potential, to date only two G proteins have been identi®ed which harbor naturally occurring mutations, Gsa, the activator of adenylyl cyclase and Gi2a, which is involved in several functions, including adenylyl cyclase inhibition and ion channel modulation. The gene encoding Gsa (GNAS1) may be altered by loss or gain of function mutations. Indeed, heterozygous inactivating germ line mutations in this gene cause pseudohypoparathyroidism type Ia, in which physical features of Albright hereditary osteodystrophy (AHO) are associated with resistance to several hormones, i.e. PTH, TSH and gonadotropins, that activate Gs-coupled receptors or pseudopseudohypoparathyroidism in which AHO is the only clinical manifestation. Evidence suggests that the variable and tissue-speci®c hormone resistance observed in PHP Ia may result from tissuespeci®c imprinting of the GNAS1 gene, although the Gsa knockout model only in part reproduces the human AHO phenotype. Activating somatic Gsa mutations leading to cell proliferation have been identi®ed in endocrine tumors constituted by cells in which cAMP is a mitogenic signal, i.e. GH-secreting pituitary adenomas, hyperfunctioning thyroid adenomas and Leydig cell tumors. When the same mutations occur very early in embryogenesis they cause McCune±Albright syndrome. Although these mutations would in principle confer growth advantage, studies failed to detect differences in the clinical and hormonal phenotypes, suggesting the existence of mechanisms able to counteract the activation of the cAMP pathway. Activating mutations of Gi2a have been identi®ed in a subset of ovarian, adrenal and pituitary tumors, but their prevalence and signi®cance are still controversial. Finally, although Ga subunits are the only components of the heterotrimeric GTP binding proteins which harbor known mutations, b/g subunits should be considered possible targets of genetic alterations as suggested by the frequent presence of b3 subunit variants in patients with essential hypertension.

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“…Presumably, this is primarily due to elevation of intracellular cAMP levels, because there is abundant documentation of interactions between the cAMP and GR pathways and induction of apoptosis in lymphoid cells by both. 23,[52][53][54] The mechanism of cAMP-induced apoptosis itself is unclear, but it appears to require presence of the GR, even in the absence of exogenous glucocorticoid. 23,55 Recently published findings suggest that forskolin can stimulate p53 activity, in a pathway that appears to involve a ternary complex of p53, cAMP response element binding protein (CREB), and CREB binding protein (CBP).…”

Section: Pde4 Inhibitor Induces Apoptosis In All Cells 3395mentioning

confidence: 99%

Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21WAF1/CIP1 proteins in human acute lymphoblastic leukemia cells

Ogawa

Streiff

Bugayenko

et al. 2002

Blood

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Glucocorticoids are integral to successful treatment of childhood acute lymphoblastic leukemia (ALL) and other lymphoid malignancies. A large body of data indicates that in various model systems, elevation of cyclic adenosine monophosphate (cAMP) can potentiate glucocorticoid response, although this has not been well evaluated as a potential leukemia treatment. Although cAMP analogs have been studied, little data exist regarding the potential toxicity to leukemia cells of pharmacologic elevation of cAMP levels in leukemic blasts. Using MTT assays of cell proliferation on CEM ALL cells, we found that aminophylline and other nonspecific phosphodiesterase (PDE) inhibitors suppress cell growth. This effect is replicated by the PDE4-specific PDE inhibitor rolipram, but not by specific inhibitors of the PDE1 or PDE3 classes. We found that PDE inhibitors cause increased dexamethasone sensitivity and a synergistic effect with the adenylyl cyclase activator forskolin. We observed several important cellular characteristics associated with this treatment, including elevation of cAMP, induction of p53 and p21 WAF1/CIP1 proteins, G 1 and G 2 /M cell cycle arrest, and increased apoptosis. Sensitivity to forskolin and rolipram is shared by at least 2 pediatric ALL cell lines, CEM and Reh cells. Some cell lines derived from adult-type lymphoid malignancies also show sensitivity to this treatment. These findings suggest that PDE inhibitors have therapeutic potential in human ALL and characterize the molecular mechanisms that may be involved in this response. IntroductionGlucocorticoids have been among the first known effective agents for the treatment of childhood acute lymphocytic leukemia (ALL). Despite the variety of chemotherapeutic drugs with activity in this disease, the importance of glucocorticoids consistently is highlighted by clinical data. 1,2 In particular, the results from a series of European trials have indicated that the in vivo response to an initial 7-day course of prednisone monotherapy is a highly reliable prognostic factor in childhood ALL. 3 The relationship between the expression level of glucocorticoid receptors (GRs) in leukemic blasts and clinical responses has been demonstrated repeatedly in childhood ALL. [4][5][6][7] A single-institution study demonstrated a higher induction failure rate and relapse rate in patients with lower blast GR levels. 8 The early data from a Pediatric Oncology Group study indicated an average of 9900 GR/cell in 291 patients who achieved subsequent remission induction, compared to an average of 4400 GR/cell in 13 patients who did not achieve remission status. 9 Long-term follow up showed that a higher GR expression is a favorable prognostic factor in childhood ALL, in which the 5-year event-free survival rate was 47% for patients with fewer than 8000 GR/cell, and 61% for those with more than 8000 GR/cell. 10 These clinical studies suggest that either higher GR content confers enhanced glucocorticoid susceptibility on the leukemic blasts or, alternatively, that this GR conte...

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G-Proteins: implications for pathophysiology and disease

Cited by 24 publications

References 60 publications

A population‐based approach to the investigation of osteopenia in Rett syndrome

A population‐based approach to the investigation of osteopenia in Rett syndrome

G protein mutations in endocrine diseases

Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21WAF1/CIP1 proteins in human acute lymphoblastic leukemia cells

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