Beta-catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor
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Beta-catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor. / Widlund, Hans R; Horstmann, Martin A; Price, E Roydon; Cui, Junqing; Lessnick, Stephen L; Wu, Min; He, Xi; Fisher, David E.
in: J CELL BIOL, Jahrgang 158, Nr. 6, 16.09.2002, S. 1079-87.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Beta-catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor
AU - Widlund, Hans R
AU - Horstmann, Martin A
AU - Price, E Roydon
AU - Cui, Junqing
AU - Lessnick, Stephen L
AU - Wu, Min
AU - He, Xi
AU - Fisher, David E
PY - 2002/9/16
Y1 - 2002/9/16
N2 - The transcription factor Microphthalmia-associated transcription factor (MITF) is a lineage-determination factor, which modulates melanocyte differentiation and pigmentation. MITF was recently shown to reside downstream of the canonical Wnt pathway during melanocyte differentiation from pluripotent neural crest cells in zebrafish as well as in mammalian melanocyte lineage cells. Although expression of many melanocytic/pigmentation markers is lost in human melanoma, MITF expression remains intact, even in unpigmented tumors, suggesting a role for MITF beyond its role in differentiation. A significant fraction of primary human melanomas exhibit deregulation (via aberrant nuclear accumulation) of beta-catenin, leading us to examine its role in melanoma growth and survival. Here, we show that beta-catenin is a potent mediator of growth for melanoma cells in a manner dependent on its downstream target MITF. Moreover, suppression of melanoma clonogenic growth by disruption of beta-catenin-T-cell transcription factor/LEF is rescued by constitutive MITF. This rescue occurs largely through a prosurvival mechanism. Thus, beta-catenin regulation of MITF expression represents a tissue-restricted pathway that significantly influences the growth and survival behavior of this notoriously treatment-resistant neoplasm.
AB - The transcription factor Microphthalmia-associated transcription factor (MITF) is a lineage-determination factor, which modulates melanocyte differentiation and pigmentation. MITF was recently shown to reside downstream of the canonical Wnt pathway during melanocyte differentiation from pluripotent neural crest cells in zebrafish as well as in mammalian melanocyte lineage cells. Although expression of many melanocytic/pigmentation markers is lost in human melanoma, MITF expression remains intact, even in unpigmented tumors, suggesting a role for MITF beyond its role in differentiation. A significant fraction of primary human melanomas exhibit deregulation (via aberrant nuclear accumulation) of beta-catenin, leading us to examine its role in melanoma growth and survival. Here, we show that beta-catenin is a potent mediator of growth for melanoma cells in a manner dependent on its downstream target MITF. Moreover, suppression of melanoma clonogenic growth by disruption of beta-catenin-T-cell transcription factor/LEF is rescued by constitutive MITF. This rescue occurs largely through a prosurvival mechanism. Thus, beta-catenin regulation of MITF expression represents a tissue-restricted pathway that significantly influences the growth and survival behavior of this notoriously treatment-resistant neoplasm.
KW - Animals
KW - Apoptosis
KW - Cell Division
KW - Cell Line
KW - Cytoskeletal Proteins
KW - DNA-Binding Proteins
KW - Gene Expression Regulation, Neoplastic
KW - Green Fluorescent Proteins
KW - Humans
KW - Luminescent Proteins
KW - Lymphoid Enhancer-Binding Factor 1
KW - Melanoma
KW - Melanoma, Experimental
KW - Mice
KW - Microphthalmia-Associated Transcription Factor
KW - Promoter Regions, Genetic
KW - Trans-Activators
KW - Transcription Factors
KW - Transcriptional Activation
KW - Transfection
KW - Tumor Cells, Cultured
KW - beta Catenin
U2 - 10.1083/jcb.200202049
DO - 10.1083/jcb.200202049
M3 - SCORING: Journal article
C2 - 12235125
VL - 158
SP - 1079
EP - 1087
JO - J CELL BIOL
JF - J CELL BIOL
SN - 0021-9525
IS - 6
ER -