Lung cancer is the leading cause of cancer deaths in the U.S. and worldwide. Dmp1 is a transcription factor that receives mitogenic signals from oncogenic Ras and induces Arf-, p53-dependent cell cycle arrest to prevent tumor formation. Our recent study demonstrated that the DMP1 gene is hemizygously deleted in ~40% of human non-small-cell lung carcinomas and K-ras-mediated murine lung carcinomas, especially those that retain wild-type Ink4a/Arf and/or p53. In this proposal, we will study the mechanisms and significance of physical interactions between Dmp1 (cyclin D binding myb-like protein 1) and p53, Dmp1 and YY1, and their roles in lung cancer development. We have four Specific Aims.
Aim 1 : To clarify the significance of Dmp1's interaction with p53 and YY1;
Aim 2 : To determine Dmp1's post- translational modifications and mode of nuclear localization;
Aim 3 : To create novel lung cancer models by generating doxycycline-inducible YY1-transgenic mice and crossing with Dmp1-deficient mice;
and Aim 4 : To study loss of heterozygosity (LOH) of hDMP1 and overexpression of YY1 in samples from patients with non-small-cell lung cancer and determine their prognostic values. We hypothesize that Dmp1 directly binds to p53 and competes with Mdm2-mediated ubiquitination, nuclear export, and inhibition of transcription of p53. Further, we posit that Dmp1 directly interacts with YY1 and neutralizes its activity for p53 inactivation. The Dmp1 protein could undergo sumoylation and phosphorylation for nuclear localization and subsequent activation. We hypothesize that YY1 overexpression in murine lung epithelial cells will lead to lung carcinogenesis, which might be accelerated in Dmp1-null or heterozygous backgrounds. Non-small-cell lung cancers with LOH of hDMP1 often retain wild-type INK4a/ARF and p53. They often overexpress YY1. Our preliminary studies show that LOH of hDMP1 is associated with low Ki67 index and Stage I disease of NSCLC. Thus, we anticipate that lung cancers with hDMP1 deletion and/or overexpression of YY1 might have a better prognosis than those with INK4a/ARF and/or p53 involvement. Our extensive preliminary data provide strong support for our hypotheses, and illustrate the feasibility of the approaches and techniques. Our proposed scientific team combines the needed expertise to successfully carry out each of the Specific Aims. All four specific aims we have proposed are very closely linked. We believe this work will produce important results regarding the roles of Dmp1 and p53/YY1 in pulmonary carcinogenesis. This line of inquiry has direct translational importance for a human disease of significant public-health impact. The novel lung cancer models we will create may be useful in future drug screenings for human lung cancer.
Our proposed studies will demonstrate that DMP1 activates the p53 tumor suppressor protein and inhibits the YY1 oncoprotein through direct physical interactions. We will also demonstrate that DMP1 deletion and YY1 overexpression often coexist in human lung cancer samples and that both of these molecules will be useful markers to predict the prognoses of lung cancer patients. Our novel, conditional mouse models for lung cancer may be useful in future drug screenings for human lung cancer.
|Inoue, Kazushi; Fry, Elizabeth A (2018) Aberrant expression of p16INK4a in human cancers - a new biomarker? Cancer Rep Rev 2:|
|Fry, Elizabeth A; Mallakin, Ali; Inoue, Kazushi (2018) Translocations involving ETS family proteins in human cancer. Integr Cancer Sci Ther 5:|
|Inoue, Kazushi; Fry, Elizabeth A (2018) Tumor suppression by the EGR1, DMP1, ARF, p53, and PTEN Network. Cancer Invest :1-17|
|Fry, Elizabeth A; Inoue, Kazushi (2018) Aberrant expression of ETS1 and ETS2 proteins in cancer. Cancer Rep Rev 2:|
|Inoue, Kazushi; Fry, Elizabeth A (2017) Haploinsufficient tumor suppressor genes. Adv Med Biol 118:83-122|
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|Fry, Elizabeth A; Taneja, Pankaj; Inoue, Kazushi (2017) Oncogenic and tumor-suppressive mouse models for breast cancer engaging HER2/neu. Int J Cancer 140:495-503|
|Fry, Elizabeth A; Taneja, Pankaj; Inoue, Kazushi (2016) Clinical applications of mouse models for breast cancer engaging HER2/neu. Integr Cancer Sci Ther 3:593-603|
|Wang, Jingxuan; Zhang, Xiao; Shi, Jinming et al. (2016) Fatty acid synthase is a primary target of MiR-15a and MiR-16-1 in breast cancer. Oncotarget 7:78566-78576|
|Inoue, Kazushi; Fry, Elizabeth A; Frazier, Donna P (2016) Transcription factors that interact with p53 and Mdm2. Int J Cancer 138:1577-85|
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