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J. Biol. Chem., Vol. 277, Issue 51, 49438-49445, December 20, 2002
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From the Pathology Department, Upstate Medical University,
Syracuse, New York 13210
Mirk/Dyrk1B protein kinase was shown in an
earlier study to function as a transcriptional activator of HNF1
The Transcriptional Activator Mirk/Dyrk1B Is Sequestered
by p38
/
MAP Kinase*
,
which Mirk phosphorylates at Ser249 within its
CREB (cAMP-response element-binding protein)-binding protein (CBP)
binding domain (1). The MAPK kinase MKK3 was also shown to activate
Mirk as a protein kinase, implicating Mirk in the biological response
to certain stress agents. Another MKK3 substrate, p38MAPK, is now shown
to inhibit the function of Mirk as a transcriptional activator in a
kinase-independent manner. Co-immunoprecipitation experiments
demonstrated that kinase-inactive p38AF, as well as wild-type p38,
sequestered Mirk and prevented its association with MKK3. Only the
p38 and p38
isoforms, but not the 
or 
isoforms, complexed
with Mirk. p38MAPK blocked Mirk activation of HNF1 in a
dose-dependent manner, with high levels of kinase-inactive
p38AF completely suppressing the activity of Mirk. Size
fractionation by fast protein liquid chromatography on Superdex 200 demonstrated that Mirk is not found as a monomer in vivo,
but is found within 150-700 kDa subnuclear complexes, which co-migrate
with the nuclear body scaffolding protein PML. Endogenous Mirk, p38,
and MKK3 co-migrate within 500-700-kDa protein complexes, which
accumulate when nuclear export is blocked by leptomycin B. Stable
overexpression of Mirk increases the fraction of Mirk protein and p38
protein within these 500-700 kDa complexes, suggesting that the
complexes act as nuclear depots for Mirk and p38. Sequestration of Mirk
by p38 may occur within these subnuclear complexes. Synchronization
experiments demonstrated that Mirk levels fluctuate about 10-fold
within the cell cycle, while p38 levels do not, leading to the
speculation that endogenous p38 could only block Mirk function when
Mirk levels were low in S phase and not when Mirk levels were elevated
in G0/G1. These data suggest a novel cell
cycle-dependent function for p38, suppression of the
function of Mirk as a transcriptional activator only when cells are
proliferating, and thus limiting Mirk function to growth-arrested cells.
*
This work was supported by Public Health Service Award RO1
CA67405 (to E. F.).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.
To whom all correspondence should be addressed: Upstate Medical
University, Pathology Dept., 2303 Weiskotten Hall, 750 East Adams St.,
Syracuse, NY 13210. Tel.: 315-464-7148; Fax: 315-464-8419; E-mail:
friedmae@mail.upstate.edu.
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