Role of TRAF2/GCK in melanoma sensitivity to UV-induced apoptosis

Ivanov, Vladimir N.; Kehrl, John H.; Ronai, Ze’ev

doi:10.1038/sj.onc.1203415

Cited by 37 publications

(27 citation statements)

References 59 publications

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“…Our previous studies have demonstrated the changes in TRAF2/GCK expression and activities during melanoma progression. Through the regulation of both p38 and JNK signaling TRAF2/GCK and their e ectors p38/JNK kinases and ATF2/c-Jun transcription factors were implicated in melanoma sensitivity to radiation (Ivanov et al, 2000;Ivanov and Ronai, 1999;Ronai et al, 1998). Data shown in the present study identi®es another layer of regulation, namely, the suppression of Fas expression upon p38 activation.…”

Section: Cell Linessupporting

confidence: 50%

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p38 protects human melanoma cells from UV-induced apoptosis through down-regulation of NF-κB activity and Fas expression

2000

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Identifying mechanisms that underlie the resistance of human melanoma to radiation and chemotherapy is expected to assist in developing new strategies for the treatment of this tumor type. We recently demonstrated that through up-regulation of TNFa, ATF2 increases the resistance of late stage melanoma cells to apoptosis induced by UV-irradiation. In elucidating the role of ATF2 kinases, we now demonstrate that ASK1/MKK6/ p38 elicits suppression of Fas expression. ASK1/p38 downregulates the expression of a Fas via NF-kB/SP1 site on the Fas promoter. Deletion or mutation of NFkB/SP1 within the Fas promoter abrogates p38 e ect. ASK1/p38 silences the Fas promoter by inhibition of IkBa phosphorylation ± thereby limiting NF-kB activity. Forced expression of a dominant negative form of p38 (p38-ASP) or treatment with p38 pharmacological inhibitor, SB203580, increases NF-kB activity, Fas expression and the levels of UVC-induced apoptosis in late stage melanoma cells. Inhibition of p38 activity also restored NF-kB activity and Fas expression in earlyphase melanoma cells, suggesting that p38 elicited suppression of Fas expression is not restricted to late phase melanoma. Identifying p38-mediated down-regulation of Fas expression illustrates a novel regulatory pathway by which ASK1/MKK6/p38 alters the degree and nature of the UV-induced apoptosis of melanoma cells.

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Section: Cell Linessupporting

confidence: 50%

“…This early-phase melanoma cell line exhibits low activity of JNK and NF-kB which were shown to be attributed to poor GCK expression (Ivanov et al, 2000). The WM1552 cells possess poor NF-kB and Fas activities as re¯ected in the analysis of the respective promoters (not shown).…”

Section: Low Nf-kb Activity and Poor Fas Expression Coincides With Himentioning

confidence: 92%

p38 protects human melanoma cells from UV-induced apoptosis through down-regulation of NF-κB activity and Fas expression

2000

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“…Among the GCK subfamily I kinases, we also observed NFB activation by the closest HPK1 homologue GCKR/KHS, whereas the more distantly related GCK caused only moderate NFB activation, and GLK failed to elicit any activity in COS1 cells. NFB activation by GCK-related kinases may be highly cell type-dependent as GCK and GCKR/KHS failed to affect NFB in HEK293 cells (11), whereas in melanoma cells GCK activated NFB moderately (42).…”

Section: Discussionmentioning

confidence: 99%

Caspase-mediated Cleavage of Hematopoietic Progenitor Kinase 1 (HPK1) Converts an Activator of NFκB into an Inhibitor of NFκB

Arnold¹,

Liou

Drexler³

et al. 2001

Journal of Biological Chemistry

101

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Hematopoietic progenitor kinase 1 (HPK1), a mammalian Ste20-related protein kinase, is a potent stimulator of the stress-activated protein kinases (SAPKs/JNKs). Here we report activation of NFB transcription factors by HPK1 that was independent of SAPK/JNK activation. Overexpression of a dominant-negative SEK1 significantly inhibited SAPK/JNK activation, whereas NFB stimulation by HPK1 remained unaffected. Furthermore, activation of NFB required the presence of fulllength, kinase-active HPK1, whereas the isolated kinase domain of HPK1 was sufficient for activation of SAPK/ JNK. We also demonstrate that overexpression of a dominant-negative IKK␤ blocks HPK1-mediated NFB activation suggesting that HPK1 acts upstream of the IB kinase complex. In apoptotic myeloid progenitor cells HPK1 was cleaved at a DDVD motif resulting in the release of the kinase domain and a C-terminal part. Although expression of the isolated HPK1 kinase domain led to SAPK/JNK activation, the C-terminal part inhibited NFB activation. This dominant-negative effect was not only restricted to HPK1-mediated but also to NIKand tumor necrosis factor ␣-mediated NFB activation, suggesting an impairment of the IB kinase complex. Thus HPK1 activates both the SAPK/JNK and NFB pathway in hematopoietic cells but is converted into an inhibitor of NFB activation in apoptotic cells.

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“…This activity markedly increases during tumor progression (Rutberg et al, 1994;Ivanov et al, 2000a). Members of the AP-1 family, including c-Jun, have been implicated in controlling the balance between cell survival and death (Karin and Lin, 2002;Shaulian and Karin, 2002).…”

Section: Rasmentioning

confidence: 99%