): Multiple myeloma is a malignant proliferation of plasma cells, and, as with all cancers, it is critical to understand the factors which promote its metabolism, growth and death. The investigators have demonstrated that multiple myeloma cell lines are acutely sensitive to insulin and IGF-1. Cellular responses included, phosphorylation of insulin receptor substrate-1 (IRS-1), activation of phosphatidylinositol 3- kinase (PI3-kinase), increased DNA synthesis and enhanced lactate production and glycogen synthesis. In addition, they have shown that PI3-kinase serine kinase phosphorylates IRS-1 in a hormone dependent manner. Furthermore, they have observed that the insulin receptor phosphorylates the catalytic subunit of PI3- kinase, that the phosphotyrosine phosphatase (PTPase) CD45 modulates PI3-kinase activity and that insulin and IGF-1 induce apoptosis in a myeloma cell line and that this process is PI3-kinase dependent. The objective of this research project is to examine the hypothesis that insulin and IGF-1 induce apoptosis in myeloma cells, that this process is dependent on PI3- kinase and that novel interactions between PI3- kinase lipid kinase, CD45, IRS- 1 and PI3-kinase serine kinase modulate the apoptotic process. The long-term goal of this project is to define how insulin and/or IGF-1 may be used to render multiple myeloma and/or other malignancies more susceptible to cancer therapies.
The Specific Aims to be pursued are as follows. First, they will investigate the counter-regulatory role of CD45 on insulin and IGF-1 dependent PI3- kinase activity in human myeloma cell lines. Second, they will characterize the inhibitory effect of IRS-1 serine phosphorylation on PI3- kinase activity. Third, they will investigate insulin and IGF-1 dependent apoptosis and determine how PI3-kinase regulates this process. In summary, they will investigate how insulin and IGF-1 transduce their signals in myeloma cells and delineate the mechanisms by which these hormones act to control programmed cell death. Dr. Gregory G. Freund is a bright and motivated young physician and investigator who has recently been appointed as an Assistant Professor of Pathology in the College of Medicine at the University of Illinois, Urbana-Champaign. This position has provided Dr. Freund with sizable laboratory space, generous institutional support and an outstanding Primary Sponsor in Dr. Keith W. Kelley. Dr. Kelley, who is an expert in the field of IGF-1 regulation of the hematopoietic system, has a long history of training junior faculty members and substantial grant support for the term of this award. Therefore, given the state-of-the-art research facilities at the University of Illinois and the strong institutional support of the College of Medicine and Primary Sponsor, Dr. Freund has a unique opportunity to develop into an outstanding clinician and scientist.
|Deszo, Eric L; Brake, Danett K; Kelley, Keith W et al. (2004) IL-4-dependent CD86 expression requires JAK/STAT6 activation and is negatively regulated by PKCdelta. Cell Signal 16:271-80|
|O'Connor, Jason C; Freund, Gregory G (2003) Vanadate and rapamycin synergistically enhance insulin-stimulated glucose uptake. Metabolism 52:666-74|
|Godbout, Jonathan P; Pesavento, James; Hartman, Matthew E et al. (2002) Methylglyoxal enhances cisplatin-induced cytotoxicity by activating protein kinase Cdelta. J Biol Chem 277:2554-61|
|Hartman, M E; Villela-Bach, M; Chen, J et al. (2001) Frap-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation. Biochem Biophys Res Commun 280:776-81|
|Deszo, E L; Brake, D K; Cengel, K A et al. (2001) CD45 negatively regulates monocytic cell differentiation by inhibiting phorbol 12-myristate 13-acetate-dependent activation and tyrosine phosphorylation of protein kinase Cdelta. J Biol Chem 276:10212-7|
|Godbout, J P; Cengel, K A; Cheng, S L et al. (1999) Insulin activates caspase-3 by a phosphatidylinositol 3'-kinase-dependent pathway. Cell Signal 11:15-23|
|Cengel, K A; Freund, G G (1999) JAK1-dependent phosphorylation of insulin receptor substrate-1 (IRS-1) is inhibited by IRS-1 serine phosphorylation. J Biol Chem 274:27969-74|
|Cengel, K A; Kason, R E; Freund, G G (1998) Phosphatidylinositol 3'-kinase associates with an insulin receptor substrate-1 serine kinase distinct from its intrinsic serine kinase. Biochem J 335 ( Pt 2):397-404|