Autocrine and exogenous transforming growth factor β control cell cycle inhibition through pathways with different sensitivity

Jing Wang, Natalia Sergina, Tien C. Ko, Jiangeng Gong, Michael G. Brattain

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Human colon carcinoma cells HCT116 that lack transforming growth factor β (TGF-β) type II receptor (RII) demonstrated restoration of autocrine TGF-β activity upon reexpression of RII without restoring inhibitory responses to exogenous TGF-β treatment. RII transfectants (designated RII Cl 37) had a longer lag phase relative to NEO-transfected control cells (designated NEO pool) before entering exponential growth in tissue culture. The prolonged growth arrest of RII Cl 37 cells was associated with markedly reduced cyclin-dependent kinase (CDK)2 activity. Our results demonstrate that p21 induction by autocrine TGF-β is responsible for reduced CDK2 activity, which at least partially contributes to prolonged growth arrest and reduced cell proliferation in RII Cl 37 cells. In contrast to RII transfectants, HCT116 cells transfected with chromosome 3 (designated HCT116Ch3), which bears the RII gene, restored the response to exogenous TGF-β as well as autocrine TGF-β activity. Autocrine TGF-β activity in HCT116Ch3 cells induced p21 expression as seen in RII Cl 37 cells; however, in addition to autocrine activity, HCT116Ch3 cells responded to exogenous TGF-β as decreased CDK4 expression and reduced pRb phosphorylation mediated a TGF-β inhibitory response in these cells. These results indicate that autocrine TGF-β regulates the cell cycle through a pathway different from exogenous TGF-β in the sense that p21 is a more sensitive effector of the TGF-β signaling pathway, which can be induced and saturated by autocrine TGF-β, whereas CDK4 inhibition is a less sensitive effector, which can only be activated by high levels of exogenous TGF-β.

Original languageEnglish (US)
Pages (from-to)40237-40244
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number38
DOIs
StatePublished - Sep 17 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Autocrine and exogenous transforming growth factor β control cell cycle inhibition through pathways with different sensitivity'. Together they form a unique fingerprint.

  • Cite this