Abstract

The major objective of Dr. Yun Yen's proposal is to understand the gene structure and function of ribonucleotide reductase (RR) and its role in hydroxyurea (HU)-associated resistance. HU is a simple chemotherapeutic chemical that inhibits the M2 subunit of RR. An HU-resistant phenotype has been associated with M2 overexpression.
Specific Aim 1 is to clone the genomic DNA segments containing the M1 and M2 genes from wild type and HU-resistant KB cells.
Specific Aim 2 is to study the promoter and 5' flanking regions.
Specific Aim 3 has the aim of examining the role of 9 critical amino acids that may play a mechanistic role in HU resistance.
Specific Aim 4 will focus on the development of novel RR inhibitors, and HU/nucleoside combinations to circumvent HU resistance. These studies should lead to a substantially improved understanding of RR genetic structure and mechanism of HU resistance, and also to the development of new HU analogs capable of overcoming HU resistance.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA072767-03
Application #
2895772
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Forry, Suzanne L
Project Start
1997-04-01
Project End
2002-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010

  Publications

Li, Angela Ying-Jian; Lin, Her Helen; Kuo, Ching-Ying et al. (2011) High-mobility group A2 protein modulates hTERT transcription to promote tumorigenesis. Mol Cell Biol 31:2605-17
Wang, Xiaochen; Liu, Xiyong; Li, Angela Ying-Jian et al. (2011) Overexpression of HMGA2 promotes metastasis and impacts survival of colorectal cancers. Clin Cancer Res 17:2570-80
Wang, Xiaochen; Liu, Xiyong; Xue, Lijun et al. (2011) Ribonucleotide reductase subunit p53R2 regulates mitochondria homeostasis and function in KB and PC-3 cancer cells. Biochem Biophys Res Commun 410:102-7
Zhou, Bingsen; Su, Leila; Yuan, Yate-Ching et al. (2010) Structural basis on the dityrosyl-diiron radical cluster and the functional differences of human ribonucleotide reductase small subunits hp53R2 and hRRM2. Mol Cancer Ther 9:1669-79
Li, Angela Y J; Boo, Lee Ming; Wang, Shih-Ya et al. (2009) Suppression of nonhomologous end joining repair by overexpression of HMGA2. Cancer Res 69:5699-706
Zhou, Bingsen; Mi, Shu; Mo, Xueli et al. (2002) Time and sequence dependence of hydroxyurea in combination with gemcitabine in human KB cells. Anticancer Res 22:1369-77
Ren, S; Tokes, Z A; Csipke, C et al. (2001) Inhibition of tumor cell growth by Schiff bases of hydroxysemicarbazide. Anticancer Res 21:3445-51
Zhou, B S; Tsai, P; Ker, R et al. (1998) Overexpression of transfected human ribonucleotide reductase M2 subunit in human cancer cells enhances their invasive potential. Clin Exp Metastasis 16:43-9
Zhou, B S; Ker, R; Ho, R et al. (1998) Determination of deoxyribonucleoside triphosphate pool sizes in ribonucleotide reductase cDNA transfected human KB cells. Biochem Pharmacol 55:1657-65