Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.
Conveys a signal across a cell to trigger a change in cell function or state. A signal is a physical entity or change in state that is used to transfer information in order to trigger a response.
A series of molecular signals that proceeds with an activated receptor promoting the exchange of GDP for GTP on the alpha-subunit of an associated heterotrimeric G-protein complex. The GTP-bound activated alpha-G-protein then dissociates from the beta- and gamma-subunits to further transmit the signal within the cell. The pathway begins with receptor-ligand interaction, or for basal GPCR signaling the pathway begins with the receptor activating its G protein in the absence of an agonist, and ends with regulation of a downstream cellular process, e.g. transcription.
Upregulation of hypoxia-inducible factors HIF-1 and HIF-2 is frequent in human cancers and may result from tissue hypoxia or genetic mechanisms, in particular the inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene (TSG). Tumours with VHL inactivation are highly vascular, but it is unclear to what extent HIF-dependent and HIF-independent mechanisms account for pVHL tumour suppressor activity. As the identification of novel pVHL targets might provide insights into pVHL tumour suppressor activity, we performed gene expression microarray analysis in VHL-wild-type and VHL-null renal cell carcinoma (RCC) cell lines. We identified 30 differentially regulated pVHL targets (26 of which were 'novel') and the results of microarray analysis were confirmed in all 11 novel targets further analysed by real-time RT-PCR or Western blotting. Furthermore, nine of 11 targets were dysregulated in the majority of a series of primary clear cell RCC with VHL inactivation. Three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL. The significance for pVHL function of two further genes upregulated by wild-type pVHL was initially unclear, but re-expression of GNG4 (G protein gamma-4 subunit/guanine nucleotide-binding protein-4) and MLC2 (myosin light chain) in a RCC cell line suppressed tumour cell growth. pVHL regulation of CDKN1C, SPARC and GNG4 was not mimicked by hypoxia, whereas for six of 11 novel targets analysed (including DOC-2/DAB2 and MLC2) the effects of pVHL inactivation and hypoxia were similar. For GPR56 there was evidence of a tissue-specific hypoxia response. Such a phenomenon might, in part, explain organ-specific tumorigenesis in VHL disease. These provide insights into mechanisms of pVHL tumour suppressor function and identify novel hypoxia-responsive targets that might be implicated in tumorigenesis in both VHL disease and in other cancers with HIF upregulation.
J. Biol. Chem. 270, 21765-21771 (1995)[PubMed:7665596]
With the growing awareness that the G protein beta and gamma subunits directly regulate the activities of various enzymes and ion channels, the importance of identifying and characterizing these subunits is underscored. In this paper, we report the isolation of cDNA clones encoding eight different human gamma subunits, including three novel forms designated gamma 4, gamma 10, and gamma 11. The predicted protein sequence of gamma 4 shares the most identity (60-77%) with gamma 2, gamma 3, and gamma 7 and the least identity (38%) with gamma 1. The gamma 4 is modified by a geranylgeranyl group and is capable of interacting with both beta 1 and beta 2 but not with beta 3. The predicted protein sequence of gamma 10 shows only modest to low identity (35-53%) with the other known gamma subunits, with most of the differences concentrated in the N-terminal region, suggesting gamma 10 may interact with a unique subclass of alpha. The gamma 10 is modified by a geranylgeranyl group and is capable of interacting with beta 1 and beta 2 but not with beta 3. Finally, the predicted protein sequence of gamma 11 shows the most identity to gamma 1 (76% identity) and the least identity to the other known gamma (33-44%). Unlike most of the other known gamma subunits, gamma 11 is modified by a farnesyl group and is not capable of interacting with beta 2. The close resemblance of gamma 11 to gamma 1 raises intriguing questions regarding its function since the mRNA for gamma 11 is abundantly expressed in all tissues tested except for brain, whereas the mRNA for gamma 1 is expressed only in the retina where the protein functions in phototransduction.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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