In the past few years, significant progress has been made in understanding the molecular pathology of acute promyelocytic leukemia (APL). Both cell culture and animal models support the suggestion that the PML-RARA fusion protein resulting from the t(15;17) is responsible for the development of APL. However, our studies indicate that loss of function of PML, a growth and transformation suppressor disrupted in APL may also contribute to the pathogenesis of APL. Our major focus during the previous funding period was to understand the biological function of PML. Several new findings have resulted from these studies. (a) PML plays a role in regulating cell cycle progression and apoptosis. These important properties of PML are just beginning to emerge and the molecular mechanism of how PML regulates cell cycle progression and apoptosis is not well understood. (b) Our studies suggest that PML is a substrate of cyclin-dependent kinases, this further supporting a role for PML in cell cycle control. How phosphorylation of PML affects growth suppression and apoptosis is unknown. (c) Our studies provided significant insight into the transcriptional regulatory function of PML. We found that PML represses Sp1-dependent transcription of target genes involved in the G1 to S transition, and that PML represses transactivation of NFkappaB target promoters. (d) PML recruits histone deacetylase and silences transcription of target genes by deacetylation of the promoter. We propose to continue to pursue the following specific aims: (1) to study the mechanism of PML regulation of cell cycle progression. Hypothesis to be tested: PML regulates cell cycle progression by inducing a GI arrest through its effects on transactivation of genes involved in the G1/S checkpoint. (2) To study the molecular basis of PML induced apoptosis. Hypothesis to be tested: PML induces apoptosis by (i) de-repression of the antiapoptotic effects of NFKB; (ii) induced expression of p53; and (iii) functional interaction with Bax. (3) To study PML phosphorylation and the biologic significance. Hypothesis to be tested: Phosphorylation and dephosphorylation of the PML protein play an important role in the regulation of cell cycle progression, apoptosis, and transcription regulation. Studies outlined in this proposal will provide important information toward understanding cell cycle regulation and apoptosis. Results obtained from these studies will further expand our knowledge in understanding the molecular pathology of acute promyelocytic leukemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055577-10
Application #
6533134
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mufson, R Allan
Project Start
1992-09-01
Project End
2005-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
10
Fiscal Year
2002
Total Cost
$237,687
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pathology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Li, June; Zou, Wen-Xin; Chang, Kun-Sang (2014) Inhibition of Sp1 functions by its sequestration into PML nuclear bodies. PLoS One 9:e94450
Chang, Che-Chang; Naik, Mandar T; Huang, Yen-Sung et al. (2011) Structural and functional roles of Daxx SIM phosphorylation in SUMO paralog-selective binding and apoptosis modulation. Mol Cell 42:62-74
Reineke, Erin L; Lam, Minh; Liu, Qing et al. (2008) Degradation of the tumor suppressor PML by Pin1 contributes to the cancer phenotype of breast cancer MDA-MB-231 cells. Mol Cell Biol 28:997-1006
Xu, Zhi-Xiang; Zou, Wen-Xin; Lin, Pei et al. (2005) A role for PML3 in centrosome duplication and genome stability. Mol Cell 17:721-32
Xu, Zhi-Xiang; Zhao, Rui-Xun; Ding, Tian et al. (2004) Promyelocytic leukemia protein 4 induces apoptosis by inhibition of survivin expression. J Biol Chem 279:1838-44
Xu, Zhi-Xiang; Timanova-Atanasova, Anna; Zhao, Rui-Xun et al. (2003) PML colocalizes with and stabilizes the DNA damage response protein TopBP1. Mol Cell Biol 23:4247-56
Wu, Wen-Shu; Xu, Zhi-Xiang; Hittelman, Walter N et al. (2003) Promyelocytic leukemia protein sensitizes tumor necrosis factor alpha-induced apoptosis by inhibiting the NF-kappaB survival pathway. J Biol Chem 278:12294-304
Wu, Wen-Shu; Xu, Zhi-Xiang; Chang, Kun-Sang (2002) The promyelocytic leukemia protein represses A20-mediated transcription. J Biol Chem 277:31734-9
Wu, Wen-Shu; Xu, Zhi-Xiang; Ran, Ruixiang et al. (2002) Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions. Oncogene 21:3925-33
Wu, W S; Vallian, S; Seto, E et al. (2001) The growth suppressor PML represses transcription by functionally and physically interacting with histone deacetylases. Mol Cell Biol 21:2259-68

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