No abstract

SummaryTranscription factors initiate programs of gene expression and are catalysts in downstream molecular cascades that modulate a variety of cellular processes. Pax3 is a transcription factor that is important in the melanocyte and influences melanocytic proliferation, resistance to apoptosis, migration, lineage specificity and differentiation. In this review, we focus on Pax3 and the molecular pathways that Pax3 is a part of during melanogenesis and in the melanocyte stem cell. These roles of Pax3 are emphasized during the development of diseases and syndromes resulting from either too much or too little Pax3 function. Due to its key task in melanocyte stem cells and tumors, the Pax3 pathway may provide an ideal target for either stem cell or cancer therapies.

Tumors of the exocrine pancreas have a poor prognosis. Several proteins are overexpressed in this cancer type, including the MET tyrosine kinase receptor and the transcription factor PAX6. In this report, we find that PAX6(5a), an alternately spliced variant form of PAX6, is expressed in pancreatic carcinoma cell lines at higher levels than the canonical PAX6 protein. Both protein forms of PAX6 bind directly to an enhancer element in the MET promoter and activate the expression of the MET gene. In addition, inhibition of PAX6 transcripts leads to a decline in cell growth and survival, differentiation, and a concurrent reduction of MET protein expression. These data support a model for a neoplastic pathway, where expression of a transcription factor from development activates the MET receptor, a protein that has been directly linked to protumorigenic processes of resisting apoptosis, tumor growth, invasion, and metastasis.Pancreatic cancer is an aggressive and deadly disease, with an average median survival of less than a year (1). Several genetic pathways have been identified as being active in the progression of this tumor, including signaling through MET (MET tyrosine kinase receptor protein). The MET gene encodes a tyrosine kinase receptor for the ligand hepatocyte growth factor/scatter factor. The MET gene produces a partially glycosylated 170-kDa precursor protein. This precursor is glycosylated further and cleaved into a 50-kDa ␣ chain and a 140-kDa ␤ chain to create a mature receptor (2). The MET receptor is essential for normal development and plays a role in cell migration, growth, survival, differentiation, angiogenesis, and tube formation/ branching morphogenesis (reviewed in Ref.3). MET has also been implicated in cancer progression and is directly involved in metastasis, resistance to apoptosis, and tumor growth.MET is expressed in the developing pancreatic bud of the embryo and marks candidate stem/progenitor cells in the embryonic and adult pancreas (4 -6). MET expression is expressed at very low levels in normal adult differentiated pancreatic cells (7). MET is overexpressed in pancreatic cancer cells and has been linked to the aggressiveness of this tumor in terms of growth, invasion, and metastasis (7-10).Although mutations in the MET locus have been identified, overexpression of MET occurs mainly due to aberrant transcriptional regulation (3). The MET gene is regulated by several transcription factors that can either activate or repress expression. Activators include HIF1 (hypoxia-induced factor 1) in response to oxygen deficiency (11), ETS1 (12), Sp1 (13), AP1 (14), Smads downstream of transforming growth factor-␤ signaling (13), and the p53 protein (15) The transcription factor PAX3 can also activate MET expression during the embryonic development of muscle cells (23). PAX3 belongs to the PAX gene family, and most of what is known about these related proteins is their role during development. Only recently has the expression of PAX proteins in adult stem cells and in disease been discovered...

SummaryMelanoma is a cancer with a poorly understood molecular pathobiology. We find the transcription factors

Several key transcription factors regulate cell growth, survival, and differentiation during neural crest and melanoblast development in the embryo, and these same pathways may be reactivated in tumors arising from the progenitors of these cells. The transcription factors PAX3 and FOXD3 have essential roles in melanoblasts and melanoma. In this study, we define a regulatory pathway where FOXD3 promotes the expression of PAX3. Both factors are expressed in melanoma cells and there is a positive correlation between the transcript levels of PAX3 and FOXD3. The PAX3 gene contains two FOX binding motifs within highly conserved enhancer regulatory elements that are essential for neural crest development. FOXD3 binds to both of these motifs in vitro but only one of these sites is preferentially utilized in melanoma cells. Overexpression of FOXD3 upregulates PAX3 levels while inhibition of FOXD3 function does not alter PAX3 protein levels, supporting that FOXD3 is sufficient but not necessary to drive PAX3 expression in melanoma cells. Here, we identify a molecular pathway where FOXD3 upregulates PAX3 expression and therefore contributes to melanoma progression.