transforming-growth-factor-beta and Ataxia-Telangiectasia

This manuscript is in four parts, presenting the four talks given in a symposium on normal tissue radiobiology. The first part addresses the general concept of the role of parenchymal cell radiosensitivity vs. other factors, highlighting research over the last decade that has altered our understanding of factors underlying normal tissue response. The other three parts expand on specific themes raised in the first part dealing in particular with (1) modifications of fibroblast response to irradiation in relation to the induction of tissue fibrosis, (2) the use of the linear-quadratic equation to model the potential benefits of using different means (both physical and biologic) of modifying normal tissue response, and (3) the specific role of the growth factor TFG-beta1 in normal tissue response to irradiation. The symposium highlights the complexities of the radiobiology of late normal tissue responses, yet provides evidence and ideas about how the clinical problem of such responses may be modified or alleviated.

Topics: Animals; Ataxia Telangiectasia; Cell Differentiation; Cell Survival; Cytokines; Diffusion of Innovation; Dose Fractionation, Radiation; Dose-Response Relationship, Radiation; Fibroblasts; Fibrosis; Humans; Linear Models; Lung; Mice; Mice, SCID; Models, Biological; Organ Specificity; Radiation Injuries; Radiation Tolerance; Radiobiology; Rats; Relative Biological Effectiveness; Transforming Growth Factor beta; Transforming Growth Factor beta1; Treatment Outcome; Up-Regulation

Cap-dependent ribosomal scanning occurs on the majority of cellular 5' UTRs. This process is severely hampered on long 5' UTRs, containing AUGs and secondary structure. These characteristics are often found in mRNAs encoding regulatory proteins like proto-oncogenes, growth factors, their receptors, and homeodomain proteins. A number of these mRNAs use an alternative mechanism of translation initiation, involving an internal ribosomal entry site (IRES). Cellular mRNAs containing a complex 5' UTR or an IRES share an intriguing characteristic: their translational efficiency can be very specifically regulated by their 5' UTR, providing post-transcriptional regulation. During embryonic development, the 5' UTRs of Antp. Ubx RAR beta 2 c-mos and c-myc regulate protein expression in a spatio-temporal manner. Translation initiation on a number of growth factor RNAs (IGFII, PDGF2, TGF beta, FGF-2, and VEGF) is specifically regulated during differentiation, growth, and stress. Furthermore, 5' UTR activity, mutations in the 5' UTR, or the occurrence of alternative 5' UTRs have been implicated in the progression of various forms of cancer. The mechanisms involved in 5' UTR mediated control are not well understood. Binding of trans-acting factors could mediate translation stimulation or repression. Furthermore, the precise localization of upstream AUGs and the activity of the cap-binding initiation factor 4E are suggested to be important for translation regulation of these mRNAs. This review focuses on 5' UTRs whose activity is regulated, the processes during which this regulation occurs, and as far as known the mechanisms involved.

Topics: 5' Untranslated Regions; Animals; Antennapedia Homeodomain Protein; Ataxia Telangiectasia; Cell Differentiation; DNA-Binding Proteins; Drosophila Proteins; Endothelial Growth Factors; Eukaryotic Initiation Factor-4E; Fibroblast Growth Factor 2; Gene Expression Regulation, Developmental; Genes, mos; Genes, myc; Homeodomain Proteins; Humans; Insulin-Like Growth Factor II; Leukemia; Lymphokines; Male; Nuclear Proteins; Peptide Initiation Factors; Prostatic Neoplasms; Protein Biosynthesis; Receptors, Retinoic Acid; RNA, Messenger; Transcription Factors; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Xenopus

Apoptosis is a genetically controlled response by which eukaryotic cells undergo programmed cell death. This phenomenon plays a major role in developmental pathways (1), provides a homeostatic balance of cell populations, and is deregulated in many diseases including cancer. Control of cell number is determined by an intricate balance of cell death and cell proliferation. Accumulation of cells through suppression of death can contribute to cancer and to persistent viral infections, while excessive death can result in impaired development and in degenerative diseases. Identification of genes that control cell death, and understanding of the impact of apoptosis in both development and disease has advanced our knowledge of apoptosis in the past few years. There appears to be a linkage between apoptosis and cell cycle control mechanisms. Elucidating the mechanisms that link cell cycle control with apoptosis will be of key importance in understanding tumour progression and designing new models of effective tumour therapy.

Topics: Animals; Apoptosis; Ataxia Telangiectasia; Caspase 1; Cell Cycle; Cyclin-Dependent Kinases; Cysteine Endopeptidases; fas Receptor; Gene Expression Regulation; Genes, Tumor Suppressor; Humans; Proto-Oncogene Proteins c-bcl-2; Retinoblastoma Protein; Transforming Growth Factor beta; Tumor Suppressor Protein p53