Abstract

Phorbol ester tumor promoters and epidermal growth (EGF) elicit a similar range of responses in cultured cells. The interaction of the tumor promoter TPA with cell surface-disposed EGF receptors suggests the possibility that phorbol esters and EGF induce their biological effects through a similar mechanism. EGF has been shown in cultured mouse cells to greatly increase the appearance of cDNA molecules homologous to VL30 genes, a family of moderately repetitive DNA sequences with many of the structural characteristics of retroviruses and transposon elements. The VL30 genes also contain long terminal repeats (LTR's) which have been shown to have characteristics of gene enhancers and insertion elements, and have been shown to be responsible for oncogenesis in some systems by insertion near cellular oncogene sequences. A major goal of this proposal is to examine the role of both the phorbol esters and EGF in the induction of transcriptional activity of VL30 (and other EGF-inducible genes) and to determine whether induction of VL30-specific RNA sequences results in the insertion of VL30 DNA elements into novel chromosomal sites. Detection of VL30 gene insertion will be made by Southern blotting of restriction endonuclease-digested DNA and hybridization to nick-translated VL30 cDNA. Appearance of VL30 in novel chromosomal sites will be tested in cultured cell lines and mouse primary epidermal cell cultures after continuous exposure to EGF and/or TPA. Transposition of VL30 elements will also be tested in papillomas and carcinomas of mouse skin following initiation by DMBA and promotion by TPA. Potential problems in detection, which may result from VL30 redundancy in the genome, will be overcome by transplantation of single VL30 genes (e.g., mouse) to heterologous cells (e.g., rat). Analysis of specific poly (A)+ molecules induced by EGF and TPA should indicate the similarities and dissimilarities of each compound in eliciting a biological response. The time of appearance of specific poly(A)+ molecules should indicate whether the two compounds may act at similar cellular sites. Our continuing structural analysis of intracellular processed EGF molecules and the effects of their microinjection on induction of specific genes should elucidate the role of EGF processing in the biological activity of EGF.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039360-02
Application #
3178222
Study Section
Pathology B Study Section (PTHB)
Project Start
1984-07-01
Project End
1986-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722

  Publications

Iordanov, M S; Kirsch, J D; Ryabinina, O P et al. (2005) Recruitment of TRADD, FADD, and caspase 8 to double-stranded RNA-triggered death inducing signaling complexes (dsRNA-DISCs). Apoptosis 10:167-76
Iordanov, M S; Ryabinina, O P; Schneider, P et al. (2005) Two mechanisms of caspase 9 processing in double-stranded RNA- and virus-triggered apoptosis. Apoptosis 10:153-66
Iordanov, Mihail S; Sundholm, Aaron J; Simpson, Eric L et al. (2005) Cell death-induced activation of epidermal growth factor receptor in keratinocytes: implications for restricting epidermal damage in dermatitis. J Invest Dermatol 125:134-42
Iordanov, Mihail S; Choi, Remy J; Ryabinina, Olga P et al. (2002) The UV (Ribotoxic) stress response of human keratinocytes involves the unexpected uncoupling of the Ras-extracellular signal-regulated kinase signaling cascade from the activated epidermal growth factor receptor. Mol Cell Biol 22:5380-94
Newton, D L; Hansen, H J; Liu, H et al. (2001) Specifically targeting the CD22 receptor of human B-cell lymphomas with RNA damaging agents. Crit Rev Oncol Hematol 39:79-86
Iordanov, M S; Wong, J; Bell, J C et al. (2001) Activation of NF-kappaB by double-stranded RNA (dsRNA) in the absence of protein kinase R and RNase L demonstrates the existence of two separate dsRNA-triggered antiviral programs. Mol Cell Biol 21:61-72
Iordanov, M S; Ryabinina, O P; Wong, J et al. (2000) Molecular determinants of apoptosis induced by the cytotoxic ribonuclease onconase: evidence for cytotoxic mechanisms different from inhibition of protein synthesis. Cancer Res 60:1983-94
Iordanov, M S; Wong, J; Newton, D L et al. (2000) Differential requirement for the stress-activated protein kinase/c-Jun NH(2)-terminal kinase in RNAdamage-induced apoptosis in primary and in immortalized fibroblasts. Mol Cell Biol Res Commun 4:122-8
Iordanov, M S; Paranjape, J M; Zhou, A et al. (2000) Activation of p38 mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase by double-stranded RNA and encephalomyocarditis virus: involvement of RNase L, protein kinase R, and alternative pathways. Mol Cell Biol 20:617-27
Keller, D; Zeng, X; Li, X et al. (1999) The p38MAPK inhibitor SB203580 alleviates ultraviolet-induced phosphorylation at serine 389 but not serine 15 and activation of p53. Biochem Biophys Res Commun 261:464-71

Showing the most recent 10 out of 34 publications