Non-malignant and tumor-derived cells differ in their requirement for p27Kip1 in transforming growth factor-β-mediated G1 arrest

Jeffrey C H Donovan, Jeffrey M. Rothenstein, Joyce M Slingerland

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Transforming growth factor β (TGF-β) induces G1 arrest in susceptible cells by multiple mechanisms that inhibit the G1 cyclin-dependent kinases (Cdks), including Cdk2, Cdk4, and Cdk6. TGF-β treatment of early passage finite lifespan human mammary epithelial cells (HMECs) led to an accumulation of p27Kip1 in cyclin E1-Cdk2 complexes and kinase inhibition. The requirement for p27 in the G1 arrest by TGF-β was assessed by transfection of antisense p27 (ASp27) oligonucleotides into TGF-β-treated HMECs. Despite a reduction in total and cyclin E-Cdk2 bound p27 after ASp27 transfection, HMECs remained arrested in the G1 phase. Maintenance of the G1 arrest was accompanied by increased association of the Cdk inhibitor p21WAF-1/Cip-1 and the retino-blastoma family member p130Rb2 in cyclin E1-Cdk2 complexes along with kinase inhibition. In contrast to the findings in HMECs, p27 was essential for G1 arrest by TGF-β in two tumor-derived lines. ASp27 transfection into two TGF-β-responsive, cancer-derived lines was not associated with increased compensatory binding of p21 and p130 to cyclin E1-Cdk2, and these cell lines failed to maintain G1 arrest despite the continued presence of TGF-β. Progressive cell cycle deregulation leading to impaired checkpoint controls during malignant tumor progression may alter the role of p27 from a redundant to an essential inhibitor of G1-to-S phase progression.

Original languageEnglish
Pages (from-to)41686-41692
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number44
DOIs
StatePublished - Nov 1 2002
Externally publishedYes

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Transforming Growth Factors
Tumors
Cyclins
Breast
Epithelial Cells
Neoplasms
Transfection
Phosphotransferases
Cells
Cyclin E
Deregulation
Cyclin-Dependent Kinases
Antisense Oligonucleotides
G1 Phase
S Phase
Oligonucleotides
Cell Cycle
Maintenance
Association reactions
Cell Line

ASJC Scopus subject areas

  • Biochemistry

Cite this

Non-malignant and tumor-derived cells differ in their requirement for p27Kip1 in transforming growth factor-β-mediated G1 arrest. / Donovan, Jeffrey C H; Rothenstein, Jeffrey M.; Slingerland, Joyce M.

In: Journal of Biological Chemistry, Vol. 277, No. 44, 01.11.2002, p. 41686-41692.

Research output: Contribution to journalArticle

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