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J. Biol. Chem., Vol. 277, Issue 29, 26120-26127, July 19, 2002
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From the Division of Molecular Genetics, The Netherlands Cancer
Institute, Plesmanlaan 121, 1066 CX Amsterdam,
The Netherlands
The murine tumor suppressor
p19ARF (p14ARF
in humans) is thought to fulfill an important protective role in
preventing primary cells from oncogenic transformation via its action
in the p53 pathway. Several disease-implicated regulators of
p19ARF are known to date, among which are the T-box
genes TBX2, which resides on an amplicon in primary breast
tumors, and TBX3, which is mutated in the human
developmental disorder Ulnar-Mammary syndrome. Here we identify a
variant T-site, matching 13 of 20 nucleotides of a consensus T-site, as
the essential TBX2/TBX3-binding element in the human
p14ARF promoter. Mutant analysis indicates that
both the consensus T-box and a C-terminal conserved repression domain
are essential for p14ARF repression. Whereas the
core nucleotides required for interaction of the archetypal T-box
protein Brachyury with a consensus T-site are conserved in the variant
site, additional flanking nucleotides contribute to the specificity of
TBX2 binding. This is illustrated by the inability of TBX1A or Xbra to
activate via the variant p14ARF T-site.
Importantly, this suggests a hitherto unsuspected level of specificity
associated with T-box factors and corresponding recognition sites in
regulating their target genes in vivo.
The T-box Repressors TBX2 and TBX3
Specifically Regulate the Tumor Suppressor Gene
p14ARF via a Variant T-site in the Initiator*
,
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a Pioneer grant from the Dutch Organization
for Scientific Research.
§
Supported by grants from the Dutch Cancer Society.
¶
To whom correspondence should be addressed. Tel.:
31-20-512-2030; Fax: 31-20-512-2011; E-mail:
m.v.lohuizen@nki.nl.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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