Regulation of lung cancer cell growth and invasiveness by beta-TRCP.

Abstract

Beta-transducin-repeat-containing protein (beta-TRCP) serves as a substrate-recognition subunit of Skp1/Cullin/F-box (SCF)(beta-TRCP) E3 ligases, involved in regulation of several important signaling molecules. SCF(beta-TRCP) E3 ligases play a critical role in cell mitosis as well as in various signaling pathways. Here, we provide evidence to support that beta-TRCP negatively regulates cell growth and motility of lung cancer cells. With specific antibodies, we detect loss of beta-TRCP1 protein in several lung cancer cell lines. One cell line contains an inactivated mutation of the beta-TRCP1 gene. Loss of beta-TRCP1 protein is also found in subsets of lung cancer specimens. We observe that retrovirus-mediated stable expression of beta-TRCP1 in beta-TRCP1 negative cells inhibits cell growth in soft-agar and tumor formation in nude mice. Furthermore, expression of beta-TRCP1 alters cell motility, as indicated by morphological changes and a reduced level of active matrix metalloproteinase (MMP)11. Conversely, inactivation of beta-TRCP1 by specific siRNA accelerates cell invasion. Of the 10 known substrates of SCF(beta-TRCP) E3 ligases, the protein level of cell division cycle 25 (CDC25)A is clearly affected in these lung cancer cells. Cells treated with CDC25A inhibitors become less invasive. Thus, loss of beta-TRCP1 may promote both growth and cell motility of lung cancer cells, possibly through regulation of CDC25A and the MMP11 level.

• Authors: Nonggao He, Chengxin Li, Xiaoli Zhang, Tao Sheng, Sumin Chi, Kai Chen, Qian Wang, Roger Vertrees, Roberto Logrono, Jingwu Xie
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 42 Issue 1 Pg. 18-28 (Jan 2005) ISSN: 0899-1987 [Print] United States
• PMID: 15536641 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• beta-Transducin Repeat-Containing Proteins
• CDC25A protein, human
• cdc25 Phosphatases

Topics

• Humans
• Lung Neoplasms (metabolism, pathology)
• Neoplasm Invasiveness (pathology)
• beta-Transducin Repeat-Containing Proteins (metabolism)
• cdc25 Phosphatases (metabolism)