Abstract
CDC37, an essential gene in Saccharomyces cerevisiae, interacts genetically with multiple protein kinases and is required for production of Cdc28p/cyclin complexes through an unknown mechanism. We have identified mammalian p50(Cdc37) as a protein kinase-targeting subunit of the molecular chaperone Hsp90. Previously, p50 was observed in complexes with pp60(v-src) and Raf-1, but its identity and function have remained elusive. In mouse fibroblasts, a primary target of Cdc37 is Cdk4. This kinase is activated by D-type cyclins and functions in passage through G1. In insect cells, Cdc37 is sufficient to target Hsp90 to Cdk4 and both in vitro and in vivo, Cdc37/Hsp90 associates preferentially with the fraction of Cdk4 not bound to D-type cyclins. Cdc37 is coexpressed with cyclin D1 in cells undergoing programmed proliferation in vivo, consistent with a positive role in cell cycle progression. Pharmacological inactivation of Cdc37/Hsp90 function decreases the half-life of newly synthesized Cdk4, indicating a role for Cdc37/Hsp90 in Cdk4 stabilization. This study suggests a general role for p50(Cdc37) in signaling pathways dependent on intrinsically unstable protein kinases and reveals a previously unrecognized chaperone-dependent step in the production of Cdk4/cyclin D complexes.
Original language | English (US) |
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Pages (from-to) | 1491-1502 |
Number of pages | 12 |
Journal | Genes and Development |
Volume | 10 |
Issue number | 12 |
DOIs | |
State | Published - 1996 |
Externally published | Yes |
Keywords
- Cyclin-dependent kinase
- D-type cyclin
- Hsp90
- molecular chaperone
- p50(Cdc37)
ASJC Scopus subject areas
- Genetics
- Developmental Biology