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HORMONES AND SIGNALING

The ERK pathway involves positive and negative regulations of HT-29 colorectal cancer cell growth by extracellular zinc

¹Department of Biotechnology, College of Engineering, and ²Protein Network Research Center, Yonsei University, Seoul 120-752; ³Laboratory of Molecular Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 136-706; and ⁴Department of Oral Biology, College of Dentistry, Yonsei University, Seoul 120-752, South Korea

Submitted 28 January 2003 ; accepted in final form 17 June 2003

Dietary zinc is an important trace element in the body and is related to both cell proliferation and growth arrest. A recent study found that extracellular zinc-sensing receptors trigger intracellular signal transduction in HT-29 human colorectal cancer cells. However, the signaling mechanism causing this growth regulation by extracellular zinc is not clearly understood. At 10- and 100-µM levels of ZnCl₂ treatment, HT-29 cell growth and proliferation increased and decreased, respectively, in a minimally serum-starved medium (MSSM). A lack of significant increase in intracellular zinc levels after zinc treatment suggested that this differential growth regulation of HT-29 cells by extracellular zinc is acquired by receptor-mediated signal transduction. Moreover, this zinc-induced growth regulation was differentially affected by PD-98059, suggesting the involvement of the ERK pathway. Transient ERK activation and subsequent cyclin D1 induction were observed on adding 10 µM ZnCl₂ in MSSM in the presence of cell proliferation. On the other hand, prolonged ERK activity was observed with a subsequent increase of cyclin D1 and p21^Cip/WAF1 on adding 100 µM ZnCl₂ in MSSM, and this was associated with nonproliferation. Moreover, this ERK activation and cyclin D1 and p21^Cip/WAF1 induction were abolished by PD-98059 pretreatment. The differential regulations of cell growth, ERK activities, and cyclin D1 and p21^Cip/WAF1 inductions were also observed in serum-enriched medium containing higher zinc concentrations. Therefore, differential cell cycle regulator induction occurs by a common ERK pathway in the differential growth regulation of HT-29 cells by extracellular zinc.

signal transduction; extracellular signal-regulated kinase; p21^Cip/WAF1

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