Despite progress made over the past few years which revealed the role of B-Raf, N-Ras and Pten in melanoma development, our understanding of the mechanisms underlying the ability of melanoma, among the most aggressive human cancers, to resist treatment and metastasize is not sufficiently advanced. Our studies on the transcription factor ATF2 suggest its oncogenic role in melanoma. Inhibition of ATF2 by competing peptides or natural compounds efficiently blocks melanoma development in xenografts, although we still do not understand mechanisms underlying ATF2's contribution to melanoma development. Using mouse models in which ATF2 is transcriptionally inactivated in melanocytes (ATF2 mutants) we have obtained preliminary results that point to the critical role ATF2 plays in melanoma development. The cross of ATF2 mutant mice with the Tyr:N-RasQ61K INK4a-/- strain which develop metastatic melanoma, abolished melanoma development in all but 1 out of 22 mice. These findings provide the first genetic-based evidence for ATF2's role in melanoma formation and form the basis of our hypothesis that ATF2 functions as an oncogene to promote melanoma development. Initial analysis of melanocytes identified a set of pigmentation genes, including MITF, MC1R, Silver, DCT and TYRP1, whose expression is altered in the absence of functional ATF2. Inhibition of ATF2 in melanoma reduced the expression of these pigmentation genes, which was more pronounced after UV- irradiation. These initial findings point to the important role ATF2 plays in control of pigmentation genes following UV-exposure, a physiologically relevant stimuli in melanocytes transformation. We propose to use melanoma mouse models that recapitulate the genetic changes seen in human melanoma (N-ras, Pten or B- Raf mutants) in order to determine the requirement and mechanism underlying ATF2 function in melanoma development. We will therefore: (1) establish ATF2 mutant mice on the background of (i) N-RasQ61K Cdkn2a-/- (ii) B-RafV600E/Cdkn2a-/-, and (iii) B-RafV600E Pten-/- mice - to determine ATF2's role in melanoma development and progression. These mice will be also used in subsequent aims. (2) Since both the pigmentation program and ATF2 are induced by UV-irradiation, we will determine mechanisms underlying the regulation of MITF and select pigmentation genes in melanocytes and melanomas prior and after exposure to UV-irradiation, and assess the importance of this regulation for melanocytes and melanoma biology in tissues of B-Raf/ATF2 and N-Ras/ATF2 mutant mice. (3) Using tumors and melanocytes established in aim 1 we will characterize genes regulated by ATF2 which contribute to melanoma development. Successful completion of these studies will provide significant advances to our understanding of mechanisms underlying melanoma development and the role of ATF2 in this process.
This grant will extend our studies on the role of ATF2, a transcription factor and DNA damage response protein in melanoma development and progression. Our preliminary results point to the function of ATF2 as an oncogene in malignant melanoma, using genetic mouse models, as well as to the role of ATF2 in the regulation of key pigmentation genes, including MITF. Our proposed studies will extend the use of relevant mouse melanoma models to assess ATF2 role in melanoma development and to identify and characterize the mechanisms underlying ATF2 role in the development of this tumor type.
|Claps, Giuseppina; Cheli, Yann; Zhang, Tongwu et al. (2016) A Transcriptionally Inactive ATF2 Variant Drives Melanomagenesis. Cell Rep 15:1884-92|
|Scortegagna, Marzia; Kim, Hyungsoo; Li, Jian-Liang et al. (2014) Fine tuning of the UPR by the ubiquitin ligases Siah1/2. PLoS Genet 10:e1004348|
|Scortegagna, M; Ruller, C; Feng, Y et al. (2014) Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma. Oncogene 33:4330-9|
|Varsano, Tal; Lau, Eric; Feng, Yongmei et al. (2013) Inhibition of melanoma growth by small molecules that promote the mitochondrial localization of ATF2. Clin Cancer Res 19:2710-22|
|Qi, Jianfei; Kim, Hyungsoo; Scortegagna, Marzia et al. (2013) Regulators and effectors of Siah ubiquitin ligases. Cell Biochem Biophys 67:15-24|
|Feng, Yongmei; Lau, Eric; Scortegagna, Marzia et al. (2013) Inhibition of melanoma development in the Nras((Q61K)) ::Ink4a(-/-) mouse model by the small molecule BI-69A11. Pigment Cell Melanoma Res 26:136-42|
|Lau, Eric; Ronai, Ze'ev A (2012) ATF2 - at the crossroad of nuclear and cytosolic functions. J Cell Sci 125:2815-24|
|Lau, Eric; Kluger, Harriet; Varsano, Tal et al. (2012) PKC? promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Cell 148:543-55|
|Shah, Meera; Bhoumik, Anindita; Goel, Vikas et al. (2010) A role for ATF2 in regulating MITF and melanoma development. PLoS Genet 6:e1001258|
|Lopez-Bergami, Pablo; Lau, Eric; Ronai, Ze'ev (2010) Emerging roles of ATF2 and the dynamic AP1 network in cancer. Nat Rev Cancer 10:65-76|
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