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Elucidating the temporal dynamics of NF-κB activation by TNF-α in melanoma

Kulkarni, R. P. and Baltimore, D. (2013) Elucidating the temporal dynamics of NF-κB activation by TNF-α in melanoma. Journal of Investigative Dermatology, 133 (S1). S227. ISSN 0022-202X. doi:10.1038/jid.2013.105.

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Melanoma is a heterogeneous disease resulting from dysregulation of molecular pathways, leading to poorly controlled tumor growth and metastasis if the cancer is not surgically excised in time. NF- κB is a critical transcription factor which underlies several key pathways of cellular growth, though its contribution in melanoma is not well elucidated. TNF-α is a cytokine which activates NF-κB by targeting the IκB inhibitor to the proteasome for degradation. Recent work has suggested that the melanoma stem-like state is directly dependent on TNF-α activity, further stressing the importance of this pathway in melanoma. We have found that TNF-α activation of NF-κB causes transcription of several genes, including A20, NFKBIA, and NFKBIE, which is regulated in a temporal fashion and is concentration dependent. Furthermore, this activation can be modulated through pharmacologic agents including bortezomib, which blocks proteasome degradation of IκB, thereby delaying or preventing TNF-α activity. We have also generated a fluorescent lentiviral-based reporter system for directly observing NF-κB protein expression and localization (through a p65-fluorescent protein fusion) in the cytoplasm and nucleus in order to better elucidate the dynamics of NF-κB activity in melanoma and are concurrently working to model these dynamics. The NF-κB pathway represents an important aspect in melanoma pathogenesis and our work serves to elucidate the mechanism of this activation which may be useful in developing novel strategies to block growth.

Item Type:Article
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Baltimore, D.0000-0001-8723-8190
Additional Information:© 2013 Society for Investigative Dermatology.
Issue or Number:S1
Record Number:CaltechAUTHORS:20130612-134853720
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Official Citation:Pigmentation & Melanoma J Invest Dermatol 133: S222-S242; doi:10.1038/jid.2013.105
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:38925
Deposited By: Ruth Sustaita
Deposited On:12 Jun 2013 21:22
Last Modified:09 Nov 2021 23:41

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