Both retinoids and the mannose 6-phosphate/insulin-like growth factor-II (M6P/IGF2) receptor have been shown to play fundamental roles in the control of cell growth in development and oncogenesis. Recent work has discovered that retinoic acid (RA) binds to the M6P/IGF2 receptor with high affinity, leading to alteration of the primary functions of the receptor and suppression of cell growth. These findings suggest that M6P/IGF2 receptor mediates a novel RA response pathway that may be important in cell growth regulation. However, the molecular mechanism underlying this pathway remains largely unknown. Thus, the overall goal of this proposal is to understand how RA interacts with the M6P/IGF2 receptor and the role of this interaction in cell growth regulation. The key questions that we wish to address are: 1) Where is the functional domain of the receptor protein responsible for retinoid binding? 2) What is the authentic biological consequence of the interaction? and 3) How do they work? Accordingly, the specific aims of this application are: (1) To identify the retinoid binding site of the M6P/IGF2 receptor; (2) To extend the understanding of the biological consequence of the RA-M6P/IGF2R interaction. (3) To identify the biochemical processes responsible for the biological effect of RA-M6P/IGF2R interaction. Our general approach is to create a mutant M6P/IGF2R that fails to bind RA and then assess differences of functional responses to RA between the cells expressing wild-type M6P/IGF2R and those with the mutant receptor. The principal methods to be used include protein mutagenesis, photoaffinity labeling, amino acid sequence analysis, ligand binding assay, immuno-detection, enzymatic assay and morphological analysis. Significance This project will provide fundamental information about how retinoids interact with the M6P/IGF2 receptor and shed light on the role of this novel retinoid-response pathway in regulation of cell growth. This knowledge may lead to novel or more effective therapeutic and preventive approaches for cancer and developmental defects.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA079553-01
Application #
2726421
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Program Officer
Smith, Philip F
Project Start
1999-01-01
Project End
2002-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Lai, Liangxue; Kang, Jing X; Li, Rongfeng et al. (2006) Generation of cloned transgenic pigs rich in omega-3 fatty acids. Nat Biotechnol 24:435-6
Chen, Zhihong; Ge, Yinlin; Kang, Jing X (2004) Down-regulation of the M6P/IGF-II receptor increases cell proliferation and reduces apoptosis in neonatal rat cardiac myocytes. BMC Cell Biol 5:15
Kang, Jing X (2003) The importance of omega-6/omega-3 fatty acid ratio in cell function. The gene transfer of omega-3 fatty acid desaturase. World Rev Nutr Diet 92:23-36
Ge, Yinlin; Wang, Xiaoying; Chen, Zhihong et al. (2002) Gene transfer of the Caenorhabditis elegans n-3 fatty acid desaturase inhibits neuronal apoptosis. J Neurochem 82:1360-6
Xie, Suqing; Kang, Jing X (2002) Differential expression of the mannose 6-phosphate/ insulin-like growth factor-II receptor in human breast cancer cell lines of different invasive potential. Med Sci Monit 8:BR293-300
Ge, Yinlin; Chen, Zhihong; Kang, Zhao B et al. (2002) Effects of adenoviral gene transfer of C. elegans n-3 fatty acid desaturase on the lipid profile and growth of human breast cancer cells. Anticancer Res 22:537-43
Chen, Zhihong; Ge, Yinlin; Landman, Natalie et al. (2002) Decreased expression of the mannose 6-phosphate/insulin-like growth factor-II receptor promotes growth of human breast cancer cells. BMC Cancer 2:18
Kang, Z B; Ge, Y; Chen, Z et al. (2001) Adenoviral gene transfer of Caenorhabditis elegans n--3 fatty acid desaturase optimizes fatty acid composition in mammalian cells. Proc Natl Acad Sci U S A 98:4050-4
Zang, Y; Beard, R L; Chandraratna, R A et al. (2001) Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells. Cell Death Differ 8:477-85
Kang, J X; Bell, J; Beard, R L et al. (1999) Mannose 6-phosphate/insulin-like growth factor II receptor mediates the growth-inhibitory effects of retinoids. Cell Growth Differ 10:591-600