Selective down-regulation of the G(q)alpha/G11alpha G-protein family in tumour necrosis factor-alpha induced cell death.
Investigations into the regulation of heterotrimeric GTP-binding protein alpha-subunits in models of tumour necrosis factor-alpha (TNF)-induced cell death, revealed the selective down-regulation of the G(q)alpha/G11alpha family of G-proteins. The human HeLa and murine L929 cells treated with recombinant human TNF for up to 24 h displayed down-regulated G(q)alpha/G11alpha family protein levels, but not G(s)alpha, G(i)alpha and G(o)alpha protein levels as determined by Western analyses. This effect of TNF was observed in a concentration--and time-dependent manner, consistent with the profiles of TNF-induced cell death observed. Moreover, the functioning of G(q)alpha/G11alpha family proteins were found to be impaired in TNF-treated cells, as measured by agonist-induced [Ca2+]i release. In contrast, G(s)alpha activity was unaltered by TNF-treatment, determined by measurement of agonist-induced intracellular cyclic AMP generation. These findings in TNF-induced cytotoxic models, indicate a novel 'cross-talk' mechanism by which TNF alters Ca2+-signalling mechanisms, which may contribute towards the apoptotic and necrotic cell death.
Pollock
V P
VP
Department of Biomedical Sciences, Foresterhill, University of Aberdeen, United Kingdom.
Lofthouse
E J
EJ
Jupp
O J
OJ
Gauld
S B
SB
Anderson
H M
HM
MacEwan
D J
DJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D003124:Colorimetry; D000242:Cyclic AMP / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium