Examining the control of differentiation HL-60 cells by phorbol esters helps us to understand both the block to differentiation found in human leukemias and the way in which hormones modulate normal hematopoiesis. We have presented evidence suggesting that specific activation of PK-C isoforms may be necessary to modulate HL-60 differentiation, and that this modulation may involved the differential translocation of specific PK-C isoforms to the nucleus. Once in the nucleus it is possible that PK-C may effect specific transactivating factors to modulate gene transcription and regulate differentiation. We have demonstrated that phorbol ester treatment of HL-60 cells increases the amount of the c-jun RNA which encodes for the transactivator AP-1. Phorbol esters are not physiologic differentiating agents. We have identified a differentiation inducing factor (DIF) which appears to function to differentiate HL-60 cells to macrophages. This 56,000 kDa protein is neither an interferon or interleukin. It will be the goal of this proposal to determine whether activators of HL-60 differentiation stimulate the translocation of specific PK-C isoforms to the nucleus, whether once in the nucleus specific protein phosphorylation occurs, and how differentiation agents effect the activity of specific transactivating proteins. Information gained from the experiments will greatly enhance our knowledge of the mechanisms controlling the differentiation of Hl- 60 cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042533-05
Application #
3183988
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1986-04-01
Project End
1994-03-31
Budget Start
1990-04-10
Budget End
1991-03-31
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Biggs, Joseph R; Peterson, Luke F; Zhang, Youhong et al. (2006) AML1/RUNX1 phosphorylation by cyclin-dependent kinases regulates the degradation of AML1/RUNX1 by the anaphase-promoting complex. Mol Cell Biol 26:7420-9
Biggs, Joseph R; Zhang, Youhong; Peterson, Luke F et al. (2005) Phosphorylation of AML1/RUNX1 regulates its degradation and nuclear matrix association. Mol Cancer Res 3:391-401
Zhang, Youhong; Biggs, Joseph R; Kraft, Andrew S (2004) Phorbol ester treatment of K562 cells regulates the transcriptional activity of AML1c through phosphorylation. J Biol Chem 279:53116-25
Biggs, J R; Yang, J; Gullberg, U et al. (2001) The human brm protein is cleaved during apoptosis: the role of cathepsin G. Proc Natl Acad Sci U S A 98:3814-9
Matsuguchi, T; Musikacharoen, T; Johnson, T R et al. (2001) A novel mitogen-activated protein kinase phosphatase is an important negative regulator of lipopolysaccharide-mediated c-Jun N-terminal kinase activation in mouse macrophage cell lines. Mol Cell Biol 21:6999-7009
Johnson, T R; Biggs, J R; Winbourn, S E et al. (2000) Regulation of dual-specificity phosphatases M3/6 and hVH5 by phorbol esters. Analysis of a delta-like domain. J Biol Chem 275:31755-62
Biggs, J R; Kraft, A S (1999) The role of the Smad3 protein in phorbol ester-induced promoter expression. J Biol Chem 274:36987-94
Burgess, G S; Williamson, E A; Cripe, L D et al. (1998) Regulation of the c-jun gene in p210 BCR-ABL transformed cells corresponds with activity of JNK, the c-jun N-terminal kinase. Blood 92:2450-60
Franklin, C C; Srikanth, S; Kraft, A S (1998) Conditional expression of mitogen-activated protein kinase phosphatase-1, MKP-1, is cytoprotective against UV-induced apoptosis. Proc Natl Acad Sci U S A 95:3014-9
Biggs, J R; Ahn, N G; Kraft, A S (1998) Activation of the mitogen-activated protein kinase pathway in U937 leukemic cells induces phosphorylation of the amino terminus of the TATA-binding protein. Cell Growth Differ 9:667-76

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