Nucleic Acids Research, 1995, Vol. 23, No. 12 2277-2286
© 1995
MOLECULAR BIOLOGY |
Functional domains of the heavy metal-responsive transcription regulator MTF-1
Institut für Molekularbiologie II der Universitat Zurich CH-8057 Zurich, Switzerland
* To whom correspondence should be addressed
Received January 30, 1995. Revised May 1, 1995. Accepted May 1, 1995.
Metallothionelns (MTs) constitute a class of low molecular weight, cystelne-rich, metal binding proteins which are regulated at the level of gene transcription in response to heavy metals and other adverse treatments. We have previously cloned a zinc finger factor (MTF-1) that binds specifically to heavy metal-responsive DNA sequence elements in metallothlo-nein promoters and shown that this factor is essential for basal and heavy metal-induced transcription. Here we report that the C-terminal part of MTF-1 downstream of the DNA binding zinc fingers harbours three different transactivation domains, namely an acidic domain, a proline-rich domain and a domain rich in serine and threonine. When fused to the heterologous DNA binding domain of the yeast factor GAL4 these activation domains function constitutlvely, i.e. transcription of a GAL4-drlven reporter gene is not Induced by heavy metals. In search of the region(s) responsible for metal induction, external and internal deletion mutations of mouse and human MTF-1 and chimeric valiants thereof were tested with a reporter gene driven by a metal-responsive promoter. The N-termlnal part of MTF-1 containg the zinc fingers, which are dependent on zinc for efficient DNA binding, can indeed confer a limited (3- to 4-fold) zinc-responsive transcription when fused to the heterologous activation domain of the viral VP16 protein. Another region containing the acidic and proline-rich activation domains also contributes to metal inducibllity, but only in the context of Intact MTF-1. This indicates that the activity of MTF-1 results from a complex interplay of different functional domains.
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