Function of the c-Myc antagonist Mad1 during a molecular switch from proliferation to differentiation.
Mol Cell Biol
; 17(5): 2353-9, 1997 May.
Article
en En
| MEDLINE
| ID: mdl-9111304
ABSTRACT
Mad-Max heterodimers have been shown to antagonize Myc transforming activity by a mechanism requiring multiple protein-protein and protein-DNA interactions. However, the mechanism by which Mad functions in differentiation is unknown. Here, we present evidence that Mad functions by an active repression mechanism to antagonize the growth-promoting function(s) of Myc and bring about a transition from cellular proliferation to differentiation. We demonstrate that exogenously expressed c-Myc blocks inducer-mediated differentiation of murine erythroleukemia cells without disrupting the induction of endogenous Mad; rather, high levels of c-Myc prevent a heterocomplex switch from growth-promoting Myc-Max to growth-inhibitory Mad-Max. Cotransfection of a constitutive c-myc with a zinc-inducible mad1 results in clones expressing both genes, whereby a switch from proliferation to differentiation can be modulated. Whereas cells grown in N'N'-hexamethylene bisacetamide in the absence of zinc fail to differentiate, addition of zinc up-regulates Mad expression by severalfold and differentiation proceeds normally. Coimmunoprecipitation analysis reveals that Mad-Max complexes are in excess of Myc-Max in these cotransfectants. Moreover, we show that the Sin-binding, basic region, and leucine zipper motifs are required for Mad to function during a molecular switch from proliferation to differentiation.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fosfoproteínas
/
Proteínas Fúngicas
/
Proteínas Nucleares
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Proteínas Portadoras
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Proteínas Proto-Oncogénicas c-myc
/
Proteínas de Saccharomyces cerevisiae
Límite:
Humans
Idioma:
En
Revista:
Mol Cell Biol
Año:
1997
Tipo del documento:
Article
País de afiliación:
Estados Unidos