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Am J Physiol Cell Physiol (May 7, 2003). doi:10.1152/ajpcell.00115.2003
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Submitted on March 28, 2003
Accepted on May 1, 2003

G{alpha}13-MEDIATED TRANSFORMATION AND APOPTOSIS IS PERMISSIVELY DEPENDENT ON BASAL ERK ACTIVITY

Vyacheslav A Adarichev1, Rita Vaiskunaite1, Jaixin Niu1, Irina V Balyasnikova2, and Tatyana A Voyno-Yasenetskaya1*

1 Department of Pharmacology, University of Illinois, Chicago, Il, USA
2 Department of Anesthesiology, University of Illinois, Chicago, Il, USA

* To whom correspondence should be addressed. E-mail: tvy{at}uic.edu.

We have previously reported that alpha subunit of heterotrimeric G13 protein induces either mitogenesis and neoplastic transformation or apoptosis in a cell-dependent manner. Here, we analyzed which signaling pathways are equired for G{alpha}13-induced mitogenesis or apoptosis using a novel mutant of G{alpha}13. We have identified that in human cell line LoVo, the mutation encoding substitution of Arg260 to stop codon in mRNA of G{alpha}13-subunit produced a mutant protein (G{alpha}13-T) that lacks C-terminus and is endogenously expressed in LoVo cells as a polypeptide of 30 kD. We have found that G{alpha}13-T lost its ability to promote proliferation and transformation but retained its ability to induce apoptosis. We have found that full-length G{alpha}13 could stimulate Elk1 transcription factor, whereas truncated G{alpha}13 lost this ability. G{alpha}13-dependent stimulation of Elk1 was inhibited by dominant negative MEK but not by dominant negative MEKK1. Similarly, MEK inhibitor PD98059 blocked G{alpha}13-induced Elk1 stimulation, whereas JNK inhibitor SB203580 was ineffective. In Rat-1 fibroblasts, G{alpha}13-induced cell proliferation and foci formation were also inhibited by dominant negative MEK and PD98059 but not by dominant negative MEKK1 and SB203580. Whereas G{alpha}13-T alone did not induce transformation, co-expression with constitutively active MEK partially restored its ability to transform Rat-1 cells. Importantly, full-length but not G{alpha}13-T could stimulate Src kinase activity. Moreover, G{alpha}13-dependent stimulation of Elk1, cell proliferation, and foci formation were inhibited by tyrosine kinase inhibitor, genistein, or by dominant negative Src kinase, suggesting the involvement of Src-dependent pathway in the G{alpha}13-mediated cell proliferation and transformation. Importantly, truncated G{alpha}13 retained its ability to stimulate apoptosis signal-regulated kinase ASK1 and c-Jun terminal kinase, JNK. Interestingly, the apoptosis induced by G{alpha}13-T was inhibited by dominant negative Ask1 or by SB203580.




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