1,721,005 research outputs found
Oncogenic role of heterotrimeric G proteins
No full textMutations that constitutively activate the α chains of G(s) and G(i2) by inhibiting their intrinsic GTPase activity are present in human endocrine tumours. The gsp oncogene is mainly found in pituitary GH secreting tumours and thyroid hyperfunctioning adenomas, where it induces a constitutive activation of the adenylyl cyclase-cAMP pathway. In pituitary and thyroid cells, this signal leads to abnormal proliferation and a persistent activation of differentiated functions. The gip2 oncogene has been identified in tumours of the ovary and adrenal cortex. Although the mechanisms of the oncogenic action of mutationally activated α(i2) are less clear than those of α(s), the protein can induce transformation of certain cell types. At least five other α chains, which share with α(s) and α(i2) common structural and functional mechanisms of GTP hydrolysis, activate mitogenic pathways leading to transformation. In addition, the G protein βγ subunits clearly control signals involved in cell growth. So far, there is no evidence for mutations of these molecules in human tumours. Further studies will tell us whether at present we know of only two members of a much larger family of G protein oncogenes
Mechanisms of signal transduction at the dopaminergic D2 receptor
No full textD2 dopamine receptor activation induces inhibition of adenylate cyclase, with a rapid decrease of cAMP levels, and an ensuing blockade of IP3-dependent release of Ca2+ from intracellular stores. K+ channels are concomitantly activated and Ca2+ channels are possibly also inhibited. The increased K+ conductance causes hyperpolarization, which may be responsible for the abolition of Ca2+ action potentials and [Ca2+], fluctuations occurring both at rest and after activation of receptors coupled to PIP2 hydrolysis. Lucia Vallar and Jacopo Meldolesi analyse this spectrum of intracellular signals which might be sufficient to sustain inhibition of secretion in pituitary lactotroph cells and possibly the other effects of D2 receptors in other cell systems
Expression of mutationally activated Gαs stimulates growth and differentiation of thyroid FRTL5 cells
No full textThe α subunit of the GTP-binding protein Gs mediates hormonal stimulation of adenylyl cyclase. Human pituitary and thyroid tumours harbour mutations of Gαs that constitutively activate the protein by inhibiting its intrinsic GTPase activity. We have investigated the mitogenic action of mutationally activated αs in thyroid FRTL5 cells, a cell line dependent upon thyroid-stimulating hormone (TSH) for both growth and differentiation. Introduction of αs carrying the substitution of glutamine-227 with leucine (Q227Lαs) by retroviral infection of FRTL5 cells resulted in the expected stimulation of membrane adenylyl cyclase activity and in increased intracellular accumulation of cAMP. Measurements of cytosolic Ca2+ levels did not detect any concomitant effect on the polyphosphoinositide-Ca2+ signalling pathway. Expression of Q227Lαs conferred to FRTL5 cells the ability to synthesize DNA in the absence of TSH, as revealed by [3H]thymidine incorporation experiments, and to proliferate independently of the mitogenic hormone, although with a rate of growth slower than that observed with TSH stimulation. The effect of Q227Lαs on cell proliferation was associated with the constitutive activation of iodide uptake. The results indicate that expression of mutationally activated Gαs is sufficient to bypass the requirement for TSH and promotes autonomous growth and activation of thyroid-specific differentiated functions in FRTL5 cells
G protein oncogenes in acromegaly
No full textG-proteins belong to a family of proteins which share the common properties of GTP binding and hydrolysis. Heterotrimeric G-proteins are composed of α-, β- and γ-subunits. The α-subunit which differs from one G-protein to another contains the GDP/GTP binding site and has intrinsic GTPase activity. The receptor occupancy causes displacement of bound GDP by GTP, dissociation of free βγ-dimer and α-GTP complex, interaction of the activated α-GTP complex with intraceilular effectors, such as enzymes and ion channels. The turn off of the reaction is due to the GTPase activity which causes the hydrolysis of GTP to GDP. G-proteins are essential for transferring hormonal signals from cell surface receptors to intracellular effectors. Since G-proteins generate intracellular effectors involved in cell growth, G-protein genes have the propensity to be converted into oncogenes. In fact, mutations in the α-subunit of Gs (the G-protein involved in the activation of adenylyl cyclase) have been demonstrated in 40% of human GH secreting pituitary adenomas. Single amino acid substitutions replacing Arg 201 with either Cys or His or Gln 227 with either Arg or Leu cause constitutive activation of adenylyl cyclase by inhibiting GTPase (gsp oncogene). The same mutations were identified in about 10% of thyroid adenomas and in the McCune-Albright syndrome
Independent regulation of Rap1 and mitogen-activated protein kinase by the alpha chain of Go
No full textReceptors coupled to G(i/o) proteins stimulate the mitogen-activated protein kinase (MAPK) cascade. The intracellular pathways linking the alpha chains of these G proteins to MAPK activation are not completely understood. One of the signaling molecules which has been suggested to act downstream of Galpha(i/o) is the small G protein Rap1. We investigated the role of Rap1 in MAPK stimulation by Galpha(o) in Chinese hamster ovary (CHO) cells. Our previous results have shown that in this cell system activated Galpha(o) strongly potentiates the MAPK response to the epidermal growth factor (EGF) receptor. Rap1 regulation was examined in cells transfected with Rap1 and wild-type Galpha(o) or the activated mutant Galpha(o)-Q205L. Immunocytochemical analysis detected both Rap1 and the Galpha(o) subunit at the plasma membrane as well as on perinuclear cytoplasmic vesicles. Expression of wild-type Galpha(o) had no significant effect on the levels of activated Rap1. In contrast, Galpha(o)-Q205L virtually abolished the activation of Rap1 induced by EGF. Further experiments showed that MAPK stimulation by EGF was greatly inhibited by expression of activated Rap1, suggesting that Rap1 inhibition could mediate the effect of Galpha(o) on the MAPK cascade. However, Galpha(o)-Q205L efficiently inhibited the activation of Rap1 induced by fibroblast growth factor (FGF). We have previously found that the ability of FGF to activate MAPK is not modified by Galpha(o). In addition, expression of the GAP protein RAP1GAPII blocked Rap1 activation without affecting EGF- or FGF-dependent MAPK stimulation. These findings provide evidence for independent regulation of Rap1 and MAPK by the G(o )alpha chain
- …
