Regulation of stability of cyclin-dependent kinase CDK11p110 and a caspase-processed form, CDK11p46, by Hsp90

Monika Mikolajczyk, Mark A Nelson

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

CDK11p110 (cyclin-dependent kinase 11p110, formerly known as PITSLRE) is a member of the CDK superfamily. It associates with cyclin L and is involved in the regulation of transcription and in premRNA splicing. During staurosporine-, Fas- and tumour necrosis factor α-induced apoptosis, CDK11p110, is cleaved by caspases to generate smaller 46-50 kDa proteins containing the catalytic kinase domain. Ectopic expression of the caspase-processed form CDK11P46 induces apoptosis. The mechanisms that regulate activation and stability of CDK11 isoforms are still unclear. In the present study, we demonstrate that in human melanoma cells CDK11P110 and CDK11P46 interact with Hsp90 (heat-shock protein 90) and its co-chaperone cdc37. Furthermore, we show that the treatment of cells with the Hsp90-specific inhibitor geldanamycin leads to ubiquitination and enhanced degradation of both CDK11p110 and CDK11p46 through a proteasome-dependent pathway. We also determined that geldana-mycin-triggered degradation of CDK11p46 slows down the progression of apoptosis. These results indicate that Hsp90 and cdc37 stabilize CDK11 kinase, and suggest that this stabilization is crucial for its pro-apoptotic function.

Original languageEnglish (US)
Pages (from-to)461-467
Number of pages7
JournalBiochemical Journal
Volume384
Issue number3
DOIs
StatePublished - Dec 15 2004

Fingerprint

HSP90 Heat-Shock Proteins
Cyclin-Dependent Kinases
Caspases
Apoptosis
Phosphotransferases
Degradation
Cyclins
Staurosporine
Ubiquitination
Corrosion inhibitors
Proteasome Endopeptidase Complex
Transcription
Melanoma
Catalytic Domain
Protein Isoforms
Stabilization
Tumor Necrosis Factor-alpha
Chemical activation
Cells
Proteins

Keywords

  • Apoptosis
  • Chaperone
  • Cyclin-dependent kinase 11
  • Heat-shock protein 90 (Hsp90)
  • PITSLRE
  • Proteasome

ASJC Scopus subject areas

  • Biochemistry

Cite this

Regulation of stability of cyclin-dependent kinase CDK11p110 and a caspase-processed form, CDK11p46, by Hsp90. / Mikolajczyk, Monika; Nelson, Mark A.

In: Biochemical Journal, Vol. 384, No. 3, 15.12.2004, p. 461-467.

Research output: Contribution to journalArticle

@article{e6c93bc0b2fc43feb20422b257e8510c,
title = "Regulation of stability of cyclin-dependent kinase CDK11p110 and a caspase-processed form, CDK11p46, by Hsp90",
abstract = "CDK11p110 (cyclin-dependent kinase 11p110, formerly known as PITSLRE) is a member of the CDK superfamily. It associates with cyclin L and is involved in the regulation of transcription and in premRNA splicing. During staurosporine-, Fas- and tumour necrosis factor α-induced apoptosis, CDK11p110, is cleaved by caspases to generate smaller 46-50 kDa proteins containing the catalytic kinase domain. Ectopic expression of the caspase-processed form CDK11P46 induces apoptosis. The mechanisms that regulate activation and stability of CDK11 isoforms are still unclear. In the present study, we demonstrate that in human melanoma cells CDK11P110 and CDK11P46 interact with Hsp90 (heat-shock protein 90) and its co-chaperone cdc37. Furthermore, we show that the treatment of cells with the Hsp90-specific inhibitor geldanamycin leads to ubiquitination and enhanced degradation of both CDK11p110 and CDK11p46 through a proteasome-dependent pathway. We also determined that geldana-mycin-triggered degradation of CDK11p46 slows down the progression of apoptosis. These results indicate that Hsp90 and cdc37 stabilize CDK11 kinase, and suggest that this stabilization is crucial for its pro-apoptotic function.",
keywords = "Apoptosis, Chaperone, Cyclin-dependent kinase 11, Heat-shock protein 90 (Hsp90), PITSLRE, Proteasome",
author = "Monika Mikolajczyk and Nelson, {Mark A}",
year = "2004",
month = "12",
day = "15",
doi = "10.1042/BJ20040848",
language = "English (US)",
volume = "384",
pages = "461--467",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "3",

}

TY - JOUR

T1 - Regulation of stability of cyclin-dependent kinase CDK11p110 and a caspase-processed form, CDK11p46, by Hsp90

AU - Mikolajczyk, Monika

AU - Nelson, Mark A

PY - 2004/12/15

Y1 - 2004/12/15

N2 - CDK11p110 (cyclin-dependent kinase 11p110, formerly known as PITSLRE) is a member of the CDK superfamily. It associates with cyclin L and is involved in the regulation of transcription and in premRNA splicing. During staurosporine-, Fas- and tumour necrosis factor α-induced apoptosis, CDK11p110, is cleaved by caspases to generate smaller 46-50 kDa proteins containing the catalytic kinase domain. Ectopic expression of the caspase-processed form CDK11P46 induces apoptosis. The mechanisms that regulate activation and stability of CDK11 isoforms are still unclear. In the present study, we demonstrate that in human melanoma cells CDK11P110 and CDK11P46 interact with Hsp90 (heat-shock protein 90) and its co-chaperone cdc37. Furthermore, we show that the treatment of cells with the Hsp90-specific inhibitor geldanamycin leads to ubiquitination and enhanced degradation of both CDK11p110 and CDK11p46 through a proteasome-dependent pathway. We also determined that geldana-mycin-triggered degradation of CDK11p46 slows down the progression of apoptosis. These results indicate that Hsp90 and cdc37 stabilize CDK11 kinase, and suggest that this stabilization is crucial for its pro-apoptotic function.

AB - CDK11p110 (cyclin-dependent kinase 11p110, formerly known as PITSLRE) is a member of the CDK superfamily. It associates with cyclin L and is involved in the regulation of transcription and in premRNA splicing. During staurosporine-, Fas- and tumour necrosis factor α-induced apoptosis, CDK11p110, is cleaved by caspases to generate smaller 46-50 kDa proteins containing the catalytic kinase domain. Ectopic expression of the caspase-processed form CDK11P46 induces apoptosis. The mechanisms that regulate activation and stability of CDK11 isoforms are still unclear. In the present study, we demonstrate that in human melanoma cells CDK11P110 and CDK11P46 interact with Hsp90 (heat-shock protein 90) and its co-chaperone cdc37. Furthermore, we show that the treatment of cells with the Hsp90-specific inhibitor geldanamycin leads to ubiquitination and enhanced degradation of both CDK11p110 and CDK11p46 through a proteasome-dependent pathway. We also determined that geldana-mycin-triggered degradation of CDK11p46 slows down the progression of apoptosis. These results indicate that Hsp90 and cdc37 stabilize CDK11 kinase, and suggest that this stabilization is crucial for its pro-apoptotic function.

KW - Apoptosis

KW - Chaperone

KW - Cyclin-dependent kinase 11

KW - Heat-shock protein 90 (Hsp90)

KW - PITSLRE

KW - Proteasome

UR - http://www.scopus.com/inward/record.url?scp=10944221728&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10944221728&partnerID=8YFLogxK

U2 - 10.1042/BJ20040848

DO - 10.1042/BJ20040848

M3 - Article

C2 - 15344906

AN - SCOPUS:10944221728

VL - 384

SP - 461

EP - 467

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 3

ER -