Malignant melanoma is a cancer whose incidence is rising rapidly, but the mechanism by which normal melanocytes become malignant in vivo is still little understood. In the course of melanoma progression, a fraction of cells often becomes depigmented, which reflects the loss of the balance between mitogenic activities and differentiation in those pigment cells. A key factor involved in differentiation in pigment cells is mitogenactivated protein kinase (MAPK). However, because both activation and inhibition of MAPK signaling is known to correlate with differentiation, its function in pigment cells is still unclear. We investigated the role of MAPK signaling in pigment cells using the melanomainducing receptor tyrosine kinase Xmrk. Xmrk signaling in mouse melanocytes suppressed differentiation and induced a transformed phenotype. We found that this was based on sustained MAPK activation caused by low and transient expression of MAPK-phosphatase MKP-1. The Src kinase p59Fyn was thereby identified as being crucial for the receptor-mediated suppression of differentiation by down-regulating MKP-1 expression. Our findings reveal a novel mechanism of regulating the balance between differentiation and proliferation based on a Src kinase-modified MAPK activity. Moreover, they point to a new role for Src kinases in dedifferentiation and transformation of pigment cells.Malignant melanomas consist of cells with increased mitotic activity and a lack of differentiation as well as unevenly distributed highly pigmented cells. This situation reflects in part the influence of the microenvironment, e.g. of factors produced by keratinocytes or fibroblasts, on pigmentation and cell growth. Besides other receptors several receptor tyrosine kinases (RTKs) 1 are known to be involved in cellular processes regulating pigment cell differentiation and proliferation. The c-Kit receptor plays a crucial role in embryonic development and differentiation of pigment cells, but its expression is lost frequently in melanoma cells (1). On the other hand RTKs like the fibroblast growth factor receptor, EGF receptor, Neu, and platelet-derived growth factor receptor, which are poorly expressed in melanocytes show increased expression in melanoma cells correlating with enhanced proliferation and dedifferentiation (2, 3). For all these receptors, including c-Kit, it is known that they can activate the mitogen-activated protein kinase (MAPK) pathway in a variety of different cell types. In pigment cells the MAPK pathway was found to be the crucial link between the c-Kit receptor and activation of the melanocyte-specific transcription factor Microphthalmia (Mitf) (4). Mitf is a member of the basic helix-loop-helix leucine zipper family and binds to an element termed the M-box (GTCATGT-GCT) (5), which is found in the promoter region of the genes encoding the key enzyme of melanogenesis, tyrosinase, and the tyrosinase-related protein 1. Pigment cell-specific expression of tyrosinase as well as tyrosinase-related protein 1 is predominantly regulated by Mitf...
Our data demonstrate that overexpression and activation of STAT5 enable melanoma cells to overcome cytokine-mediated antiproliferative signaling. Thus, overexpression of STAT5 can counteract IFNalpha signaling in melanoma cells, and this finally can result in cytokine-resistant and progressively growing tumor cells. These findings have significant implications for the clinical failure of IFNalpha therapy of advanced melanoma because they demonstrate that IFNalpha induces the activation of STAT5 in melanoma cells, and in STAT5-overexpressing cells, this contributes to IFNalpha resistance.
Extensive studies of primary tumors and tumor derived cell lines revealed that inappropriate activation of speci®c STATs (particularly of STAT3 and STAT5) occurs with high frequency in a wide variety of human cancers. We reported recently that the melanoma inducing EGFRrelated receptor Xmrk speci®cally induces constitutive activation of STAT5 in ®sh melanoma cells. However, little is known about the role of STAT5 in solid tumours in general and its function in melanoma in particular. Recent examinations suggest that activated STAT signalling participates in oncogenesis by stimulating cell proliferation and preventing apoptosis. As an initial approach to understanding the consequences of Xmrk induced STAT5 signalling we used the well characterized pro B-cell line Ba/F3 as a sensitive system to analyse mitogenic as well as anti-apoptotic signalling. We identi®ed STAT5 activation as being involved in both growth and survival signalling triggered by the Xmrk kinase possibly due to STAT5 induced expression of pim-1 and bcl-x. We also found a new mechanism of activation of STAT5 by receptor tyrosine kinases, whereby direct interaction of the receptor kinase domain with the STAT protein in a phosphotyrosine independent way led to activation of STAT5 in terms of DNA binding and target gene expression.
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