This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, S.-W. Articles by Lee, J.-D. Search for Related Content PubMed PubMed Citation Articles by Kim, S.-W. Articles by Lee, J.-D.

Tid1, the Human Homologue of a Drosophila Tumor Suppressor, Reduces the Malignant Activity of ErbB-2 in Carcinoma Cells

¹ Department of Immunology, The Scripps Research Institute, La Jolla, California; and ² Department of Surgery, University of California, San Francisco, California

The ErbB-2/HER-2 receptor tyrosine kinase is overexpressed in a wide range of solid human tumors. The ErbB-2 gene product is a transmembrane glycoprotein belonging to the epidermal growth factor receptor family, and its cytoplasmic domain is responsible for sending the mitogenic signals into cells. We discovered that this domain of ErbB-2 interacts with Tid1 protein, the human counterpart of the Drosophila tumor suppressor Tid56, whose null mutation causes lethal tumorigenesis during the larval stage. Tid1 also is known as a cochaperone of heat shock protein 70 (HSP70) and binds to HSP70 through its conserved DnaJ domain. We found that increased expression of Tid1 in human mammary carcinomas overexpressing ErbB-2 suppresses the expression level of ErbB-2 and attenuates the resultant ErbB-2–dependent oncogenic extracellular signal-regulated kinase 1/2 and big mitogen-activated protein kinase 1 signaling pathways leading to programmed cell death (PCD). A functional DnaJ domain of Tid1 also is required for its inhibition of ErbB-2 expression and the consequent PCD of carcinoma cells resulting from increased Tid1 expression. Importantly, ErbB-2–dependent tumor progression in animals is inhibited by increased expression of Tid1 in tumor cells. Collectively, these results suggest that Tid1 modulates the uncontrolled proliferation of ErbB-2–overexpressing carcinoma cells by reducing ErbB-2 expression and as a result suppresses the ErbB-2–dependent cancerous signaling and tumor progression. Moreover, the cochaperonic and regulatory functions of Tid1 on HSP70 most likely play an essential role in this antitumor function of Tid1 in carcinoma cells.

This article has been cited by other articles:

				S.-Y. Sohn, S.-B. Kim, J. Kim, and B.-Y. Ahn Negative regulation of hepatitis B virus replication by cellular Hsp40/DnaJ proteins through destabilization of viral core and X proteins J. Gen. Virol., July 1, 2006; 87(7): 1883 - 1891. [Abstract] [Full Text] [PDF]

				B. Lu, N. Garrido, J. N. Spelbrink, and C. K. Suzuki Tid1 Isoforms Are Mitochondrial DnaJ-like Chaperones with Unique Carboxyl Termini That Determine Cytosolic Fate J. Biol. Chem., May 12, 2006; 281(19): 13150 - 13158. [Abstract] [Full Text] [PDF]

				S.-W. Kim, M. Hayashi, J.-F. Lo, C. Fearns, R. Xiang, G. Lazennec, Y. Yang, and J.-D. Lee Tid1 Negatively Regulates the Migratory Potential of Cancer Cells by Inhibiting the Production of Interleukin-8 Cancer Res., October 1, 2005; 65(19): 8784 - 8791. [Abstract] [Full Text] [PDF]

				H.-Y. Liu, J. I. S. MacDonald, T. Hryciw, C. Li, and S. O. Meakin Human Tumorous Imaginal Disc 1 (TID1) Associates with Trk Receptor Tyrosine Kinases and Regulates Neurite Outgrowth in nnr5-TrkA Cells J. Biol. Chem., May 20, 2005; 280(20): 19461 - 19471. [Abstract] [Full Text] [PDF]