The MGSA/GRO gene was initially described as an autocrine growth factor for melanoma cells and as a growth related early response gene in fibroblasts. Subsequently, a family of these cytokines was identified including MGSA/GRO alpha, beta, gamma, and delta. the homology of the cDNAs for these four MGSA/GRO genes range from 82-93%. Many tumor cells over-express MGSA/GRO and there is evidence for tissue specific over- expression of the various subtypes of MGSA/GRO. The degradation rate of the various sub-forms appear to differ in tissues. The mRNA levels for these genes is increased when cells are treated with TPA, LPS, TNFalpha, IL-1, EGF, cycloheximide, serum, thrombin, and a number of other factors. MGSA/GRO mRNA levels are suppressed by TGFbeta in some cells. The regulation of mRNA levels by these agents appears to be the result of transcriptional effects as well as increased/decreased mRNA stability. The Hs294T malignant melanoma cell line over-expresses MGSA/GROalpha but not MGSA/GRObeta, gamma, or delta. Mutations of the NF-kappaB element markedly reduces basal transcription of a 5' MGSA/GRO CAT construct in melanoma tumor cells. In order to determine the mechanism for the elevated expression of MGSA/GRO, we will compare the basal and cytokine regulated expression of MGSA/GRO genes in melanoma to that in normal melanocytes. The goal of this study is to test the hypothesis that altered expression of MGSA/GROalpha in melanoma cells results from a combination of alterations in the level of NF-kappaB transactivation and altered mRNA stabilization. Specifically, we plan: (1) to compare the basal levels of transcription of MGSA/GRO alpha, beta, gamma, delta genes in normal and transformed melanocytes; (2) to compare the transcriptional regulation of the MGSA/GRO alpha, beta, gamma, delta genes by the cytokines IL-1, TNFalpha, TGFbeta, and by cycloheximide in these cell types, and to characterize alterations in NF-kappaB regulation of basal transcription in transformed melanocytes as compared to non-transformed melanocytes; (3) to examine the role for basal and cytokine effected MGSA/GRO in mRNA stabilization in normal melanocytes as compared to malignant melanoma cells, and (4) to examine the expression of MGSA/GRO alpha, beta, gamma, delta genes in non-malignant and malignant melanocytic lesions by in situ hybridization.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA056704-03
Application #
2097510
Study Section
Pathology B Study Section (PTHB)
Project Start
1993-02-01
Project End
1997-01-31
Budget Start
1995-02-01
Budget End
1996-01-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
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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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