The TGF-beta superfamily of cytokines regulates diverse biological functions of cellular proliferation, apoptosis, and differentiation. During carcinogenesis, the disruption of TGF-beta signaling has been shown to be critical. The underlying mechanisms of resistance to the growth inhibitory effect of TGF-beta in malignant cells involve the altered expression of either the receptors or the signaling molecules. Evidence to date, though, suggests that the most prevalent mechanism involves the receptors. Recently, we identified that the ETV6-NTRK3 fusion protein, detected in several human cancers including congenital fibrosarcoma and the secretory form of human breast cancer, suppresses TGF-beta signaling through its interaction with the TGF-beta type II receptor. Since the ETV6-NRTK3 gene is the gene fusion of the ETV6 gene in frame with the NTRK3 gene (TrkC), our study suggested that the Trk family of neurotrophin receptors, TrkA, TrkB, and TrkC, may also regulate the TGF-beta family signaling. We found that TrkC plays an essential role in tumor growth and metastasis and is expressed in human breast cancers. Suppression of TrkC expression in highly metastatic mammary carcinoma cells specifically inhibits their growth and their ability to metastasize from the mammary gland to the lung. Ectopic expression of TrkC suppressed anoikis of non-malignant mammary epithelial cells, which correlated with activation of the phosphatidylinositol-3-OH kinase/protein kinase B pathway. Furthermore, TrkC suppressed TGF-beta signaling by directly binding to the type II TGF-beta receptor (T?ORII), thereby preventing it from interacting with the type I TGF-beta receptor (TbRI). Our results have identified TrkC as a critical regulator of breast cancer cell growth and metastasis and an inhibitor of TGF-beta tumor suppressor activity. Another focus of our research has been to identify the role of inhibitory Smads (Smad6 and Smad7) in inflammation and cancer. Our observations suggest that Smad6 and/or Smad7 do not act simply as an inhibitor of signaling pathways of TGF-beta family members, but may also function as a mediator of TGF-beta signaling pathway(s). TGF-beta is a key regulator of inflammation, and deficiency of this molecule leads to extensive inflammation. However, the molecular mechanism by which the TGF-beta anti-inflammatory signal blocks pro-inflammatory signaling is not known. Recently, we demonstrated that Smad6 is a critical mediator of the TGF-beta-BMP pathway that mediates anti-inflammatory activity and negatively regulates IL-1R-TLR signals. We also found that Smad7 interacts with TAB2 and thereby blocks TNF-alpha-induced recruitment of the TAK1 complex to TNFR1 and TRAF2, mediating the TGF-beta anti-inflammatory signal to block pro-inflammatory TNF-alpha signaling. Our results indicate that pharmacological augmentation of either Smad6 or Smad7 expression may be a useful therapeutic strategy in tumors associated with inflammation.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005617-18
Application #
7337915
Study Section
(LCRC)
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Lee, H-J; Yun, C-H; Lim, S H et al. (2007) SRF is a nuclear repressor of Smad3-mediated TGF-beta signaling. Oncogene 26:173-85
Lucas, Philip J; Kim, Seong-Jin; Mackall, Crystal L et al. (2006) Dysregulation of IL-15-mediated T-cell homeostasis in TGF-beta dominant-negative receptor transgenic mice. Blood 108:2789-95
Kim, Byung-Gyu; Li, Cuiling; Qiao, Wenhui et al. (2006) Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441:1015-9
Choi, Kyung-Chul; Lee, Youn Sook; Lim, Seunghwan et al. (2006) Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor signaling through direct interaction with the adaptor Pellino-1. Nat Immunol 7:1057-65
Zhang, Qiang; Yang, Ximing J; Kundu, Shilajit D et al. (2006) Blockade of transforming growth factor-{beta} signaling in tumor-reactive CD8(+) T cells activates the antitumor immune response cycle. Mol Cancer Ther 5:1733-43
Zhang, Qiang; Jang, Thomas L; Yang, Ximing et al. (2006) Infiltration of tumor-reactive transforming growth factor-beta insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells. Prostate 66:235-47
Zhang, Qiang; Rubenstein, Jonathan N; Jang, Thomas L et al. (2005) Insensitivity to transforming growth factor-beta results from promoter methylation of cognate receptors in human prostate cancer cells (LNCaP). Mol Endocrinol 19:2390-9
Zhang, Qiang; Yang, Ximing; Pins, Michael et al. (2005) Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer. Cancer Res 65:1761-9
Ju, Eun Mi; Choi, Kyung-Chul; Hong, Seung-Hee et al. (2005) Apoptosis of mink lung epithelial cells by co-treatment of low-dose staurosporine and transforming growth factor-beta1 depends on the enhanced TGF-beta signaling and requires the decreased phosphorylation of PKB/Akt. Biochem Biophys Res Commun 328:1170-81
Yoo, Byung-Moo; Oh, Tae-Young; Kim, Young-Bae et al. (2005) Novel antioxidant ameliorates the fibrosis and inflammation of cerulein-induced chronic pancreatitis in a mouse model. Pancreatology 5:165-76

Showing the most recent 10 out of 31 publications