The chemokines, MGSA/GRO and IL-8, are constitutively expressed in melanoma and appear to play a causal role in melanoma tumor progression. Evidence to date points to a transcriptional deregulation of the MGSA/GRO chemokine, partly through an endogenous activation of the transcription factor, NF- kappaB. An immediate upstream regulatory region (IUR) is located adjacent to the NF-kappaB element and in CAT reporter assays, mutation of this element drastically decreases basal transcription. The IUR element, TCGAT, binds three proteins, approximately 100, 40 and 22kD, and the binding of these proteins cannot be eliminated or supershifted in electrophoretic mobility shift assay by antibodies to other potentially relevant transcription factors. Preliminary data point to a potential interaction between the NF-kappaB and the novel IUR binding proteins. There are four specific aims for this proposal: 1) to characterize the process by which NF-kappaB is constitutively activated in Hs294T melanoma cells and determine whether NF-kappaB activation contributes to the endogenous transcription of MGSA/GRO in melanoma; 2) to purify, sequence and clone the proteins which bind to the immediate upstream region (IUR) of the MGSA/GROalpha gene enhancer, and to determine if these factors contribute to MGSA deregulation in melanoma; 3) to characterize the prevalence or coordinate deregulation of CXC chemokines in malignant melanoma; and 4) to determine whether overexpression of the mouse homolog of MGSA in normal melanocytes is associated with tumor formation in vivo, a transgenic model will be developed. Expression of the mouse homolog of MGSA/GRO, MIP-2, will be directed by the tyrosinase promoter which will result in melanocyte specific expression. We will treat the transgenic mice with chemical carcinogens and uv irradiation to determine how continued expression of these chemokines effects melanocyte response to agents involved in tumor initiation/progression. These experiments should provide important new information about the mechanism by which deregulation of the expression of chemokines chemotactic occurs and this is key to understanding how to suppress these mediators of tumorigenesis and chronic inflammatory response.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Pathology B Study Section (PTHB)
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Shen, Grace L
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Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
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Su, Yingjun; Amiri, Katayoun I; Horton, Linda W et al. (2010) A phase I trial of bortezomib with temozolomide in patients with advanced melanoma: toxicities, antitumor effects, and modulation of therapeutic targets. Clin Cancer Res 16:348-57
Dhawan, Punita; Su, Yingjun; Thu, Yee Mon et al. (2008) The lymphotoxin-beta receptor is an upstream activator of NF-kappaB-mediated transcription in melanoma cells. J Biol Chem 283:15399-408
Yang, Jinming; Pan, Wei-Hua; Clawson, Gary A et al. (2007) Systemic targeting inhibitor of kappaB kinase inhibits melanoma tumor growth. Cancer Res 67:3127-34
Ueda, Yukiko; Su, Yingjun; Richmond, Ann (2007) CCAAT displacement protein regulates nuclear factor-kappa beta-mediated chemokine transcription in melanoma cells. Melanoma Res 17:91-103
Amiri, K I; Ha, H C; Smulson, M E et al. (2006) Differential regulation of CXC ligand 1 transcription in melanoma cell lines by poly(ADP-ribose) polymerase-1. Oncogene 25:7714-22
Yang, Jinming; Amiri, Katayoun I; Burke, James R et al. (2006) BMS-345541 targets inhibitor of kappaB kinase and induces apoptosis in melanoma: involvement of nuclear factor kappaB and mitochondria pathways. Clin Cancer Res 12:950-60
Amiri, Katayoun I; Richmond, Ann (2005) Role of nuclear factor-kappa B in melanoma. Cancer Metastasis Rev 24:301-13
Richmond, Ann; Fan, Guo Huang; Dhawan, Punita et al. (2004) How do chemokine/chemokine receptor activations affect tumorigenesis? Novartis Found Symp 256:74-89; discussion 89-91, 106-11
Amiri, Katayoun I; Horton, Linda W; LaFleur, Bonnie J et al. (2004) Augmenting chemosensitivity of malignant melanoma tumors via proteasome inhibition: implication for bortezomib (VELCADE, PS-341) as a therapeutic agent for malignant melanoma. Cancer Res 64:4912-8
Amiri, Katayoun Izadshenas; Richmond, Ann (2003) Fine tuning the transcriptional regulation of the CXCL1 chemokine. Prog Nucleic Acid Res Mol Biol 74:1-36

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