This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, J. Articles by Richmond, A. Search for Related Content PubMed PubMed Citation Articles by Yang, J. Articles by Richmond, A.

Induction of Melanoma in Murine Macrophage Inflammatory Protein 2 Transgenic Mice Heterozygous for Inhibitor of Kinase/Alternate Reading Frame¹

Veterans Affairs Medical Center and Department of Cancer Biology, Vanderbilt University School of Medicine Nashville, Tennessee 37232 [J. Y., J. L., Y. Y., C. L., A. R.], and Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [R. A. D., L. C.]

The molecular and genetic events that contribute to the genesis and progression of cutaneous malignant melanoma are poorly understood, attributable in large part to the different genetic alterations accompanying tumorigenesis. Inhibitor of kinase 4a (INK4a) is often inactivated in families with hereditary melanoma. Loss of INK4a/alternate reading frame (ARF) in mice is associated with increased incidence of other tumors such as lymphoma and fibrosarcoma. However, the incidence of melanoma in INK4a/ARF-deficient mice is very low. Our previous studies have revealed that the CXC chemokine, CXCL1, is overexpressed in human malignant melanoma cells and is linked to transformation of immortalized murine melanocytes. To study the direct role of CXCL1 on the genesis of primary melanoma lesions, transgenic mouse lines were established that express the murine homologue of CXCL1, murine macrophage inflammatory protein 2 (MIP-2), under the transcriptional control of the tyrosinase promoter/enhancer (Tyr-MIP-2) in the mice that were deficient or not deficient for INK4a/ARF. Strong MIP-2 immunoreactivity was associated with pigmented melanocytes in the hyperproliferative hair follicles in the Tyr-MIP-2 transgenic mice, and the level of MIP-2 expression was similar in both INK4a/ARF heterozygous or wild-type mice. After treatment of mice with 7,12-dimethylbenz(a)anthracene, cutaneous melanomas formed in 12% (17/145) of the Tyr-MIP-2 transgene-positive mice, whereas only 2% (3/146) of the Tyr-MIP-2 transgene-negative mice developed melanoma. When melanocytes cultured from MIP-2 transgenic mice null for INK4a/ARF were transplanted into nude mice, melanoma formation occurred in 83% (10/12) of the cases with a latency period of 3 months. However, no melanoma lesions arose in nude mice injected with INK4a/ARF -/- melanocytes, which did not express the MIP-2 transgene. Our results demonstrate that constitutive expression of MIP-2 in INK4a/ARF-deficient melanocytes facilitates formation of malignant melanoma.

This article has been cited by other articles:

				J. Yang, W.-H. Pan, G. A. Clawson, and A. Richmond Systemic Targeting Inhibitor of {kappa}B Kinase Inhibits Melanoma Tumor Growth Cancer Res., April 1, 2007; 67(7): 3127 - 3134. [Abstract] [Full Text] [PDF]

				T. Kakinuma and S. T. Hwang Chemokines, chemokine receptors, and cancer metastasis J. Leukoc. Biol., April 1, 2006; 79(4): 639 - 651. [Abstract] [Full Text] [PDF]

				J. Yang, K. I. Amiri, J. R. Burke, J. A. Schmid, and A. Richmond BMS-345541 Targets Inhibitor of {kappa}B Kinase and Induces Apoptosis in Melanoma: Involvement of Nuclear Factor {kappa}B and Mitochondria Pathways Clin. Cancer Res., February 1, 2006; 12(3): 950 - 960. [Abstract] [Full Text] [PDF]

				M.-F. Demierre and L. Nathanson Chemoprevention of Melanoma: An Unexplored Strategy J. Clin. Oncol., January 1, 2003; 21(1): 158 - 165. [Abstract] [Full Text] [PDF]

				P. Dhawan and A. Richmond Role of CXCL1 in tumorigenesis of melanoma J. Leukoc. Biol., July 1, 2002; 72(1): 9 - 18. [Abstract] [Full Text] [PDF]