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Vol. 12, No. 8, pp. 1108-1120, April 15, 1998
1 Massachusetts General Hospital Cancer Center and
2 Laboratories of Pathology and
3 Surgical Research,
Massachusetts General Hospital (MGH) and Harvard Medical School,
Charlestown, Massachusetts 02129 USA;
4 Department of
Pathology, Wake Forest University School of Medicine, Winston-Salem,
North Carolina 27157 USA; and
5 Department of Adult Oncology,
Dana-Farber Cancer Institute, Boston, Massachusetts 02115 USA
The Wilms tumor suppressor WT1 encodes a zinc finger
transcription factor that is expressed in glomerular podocytes during a
narrow window in kidney development. By immunoprecipitation and protein
microsequencing analysis, we have identified a major cellular protein
associated with endogenous WT1 to be the inducible chaperone Hsp70. WT1
and Hsp70 are physically associated in embryonic rat kidney cells, in
primary Wilms tumor specimens and in cultured cells with inducible
expression of WT1. Colocalization of WT1 and Hsp70 is evident
within podocytes of the developing kidney, and Hsp70 is recruited to
the characteristic subnuclear clusters that contain WT1. The
amino-terminal transactivation domain of WT1 is required for binding to
Hsp70, and expression of that domain itself is sufficient to induce
expression of Hsp70 through the heat shock element (HSE). Substitution
of a heterologous Hsp70-binding domain derived from human DNAJ is
sufficient to restore the functional properties of a WT1 protein with
an amino-terminal deletion, an effect that is abrogated by a point
mutation in DNAJ that reduces binding to Hsp70. These observations
indicate that Hsp70 is an important cofactor for the function of
WT1, and suggest a potential role for this chaperone during
kidney differentiation.
[Key Words: WT1; hsp70; p21; Wilms tumor; renal development; cell cycle arrest]
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