NKX3.1 codes for a prostate-specific homeodomain protein and maps to chromosome 8p21.2, a region frequently deleted in prostate cancer. Nkx3.1 has been shown to suppress cell growth in culture and to inhibit tumor growth in gene-targeted animals. Expression array analysis identified an IGF binding protein, IGFBP-3, that was substantially up regulated in response to over expression of NKX3.1. Aberrant IGF-I signaling has been reported in a variety of human cancers and elevated serum IGF-I levels are a risk factor for prostate cancer development. IGFBP-3 stimulates apoptosis, inhibits DNA synthesis and decreases in vivo tumorigenicity of prostate cancer cell lines. An NKX3.1 polymorphism exists in 11% of the population, without regard to race. Variant NKX3.1 protein coded by the polymorphic allele has reduced phosphorylation and DNA binding in vitro. The NKX3.1 polymorphism has also been shown to be a minor risk factor for prostate cancer development and disease related-mortality. In a case-control study the effect of high levels of serum IGF-I on prostate cancer risk was seen almost exclusively in men whom have at least one copy of the NKX3.1 polymorphic allele.
The data contained in this thesis shows that NKX3.1 up regulates IGFBP-3 mRNA and protein expression in prostate cancer cell lines. Stable NKX3.1 expression in PC-3 prostate cancer cells leads to the deregulation of IGF-I signaling and decreases cell proliferation. Knock down of IGFBP-3 expression in the PC-3 cells engineered to expression NKX3.1 restored IGF-I signaling and increased proliferation rate, as compared to parental PC-3 cells. The polymorphic NKX3.1 protein, NKX3.1(R52C), and the functionally equivalent mutant NKX3.1(S48A) are deficient in induction of IGFBP-3 expression. Stable expression of these variant proteins in PC-3 cells had no effect on cell proliferation and IGF-I signaling is not attenuated. We hypothesize that NKX3.1 confers local protection against IGF-I growth stimulation in prostatic epithelium by up regulating IGFBP-3. The polymorphic NKX3.1 gene has reduced capacity to induce IGFBP-3 and therefore has lost the capacity to modulate IGF-I stimulation of prostate epithelial cell proliferation, conferring increased risk of prostate cancer in men with higher levels of circulating IGF-I.
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|Advisor:||Gelmann, Edward P.|
|Commitee:||Johnson, Michael, Rechler, Matthew, Toretsky, Jeffrey, Wellstein, Anton|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 71/02, Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology, Oncology|
|Keywords:||Cell signaling, IGFBP-3, NKX3.1, Prostate, Tumor suppressors|
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