01. Gene therapy Boulikas.pdf - Gene therapy & Molecular Biology

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Boulikas: An overview on gene therapy Figure 19. Regulatory circuits involving p53. From Boulikas T (1997) Gene therapy of prostate cancer: p53, suicidal genes, and other targets. Anticancer Res 17, 1471-1506. With the kind permission of Anticancer Research. 54
Gene Therapy and Molecular Biology Vol 1, page 55 Figure 20. A summary of the apoptotic and cell cycle restrictive activities of p53. From Boulikas T (1997) Gene therapy of prostate cancer: p53, suicidal genes, and other targets. Anticancer Res 17, 1471-1506. With the kind permission of Anticancer Research. biophysical studies indicate that p53 exists as a tetramer in solution (Stenger et al., 1992). Increased levels of p53 upregulate the expression of specific genes including Cip-1/Waf-1/p21 (El-Deiry et al, 1993), GADD45 (Kastan et al, 1992), cyclin G (Okamoto and Beach, 1994), and mdm2 (Perry et al, 1993; Barak et al, 1993; Momand et al, 1992) which is induced by UV damage in a p53-dependent pathway (Perry et al, 1993). Gadd45 inhibits cell cycle progression (Papathanasiou et al, 1991). Mdm2 acts as a feedback loop for the biological functions of p53 apparently to moderate the G1/S arrest or apoptosis triggered by p53 following severe damage to DNA. Mdm2 protein associates with p53 causing p53 inactivation by preventing its sequence-specific binding to regulatory targets in DNA (Momand et al, 1992; Oliner et al, 1992). Elevated levels of Mdm2 mimic the effect of T antigen, E1B of adenovirus, E6 of HPV, which also inactivate p53 in a similar manner; overexpression of Mdm2 can block the induction of apoptosis by p53 (Chen et al, 1994). Additional genes up-regulated by p53 include human PCNA (Shivakumar et al, 1995), mouse muscle creatine kinase MCK (Zambetti et al, 1992), EGFR (Deb et al, 1994), the potent promoter of the death pathway Bax (Miyashita and Reed, 1995), and thrombospondin-1 (Dameron et al, 1994). Other cellular regulatory regions that interact with p53 include the RGC repeats in the ribosomal gene cluster (Farmer et al, 1992; Kern et al, 1992). The PCNA promoter is up-regulated in the presence of moderate amounts of wt p53; however, at higher levels of wt p53 the PCNA promoter is inhibited whereas tumorderived p53 mutants activate the PCNA promoter (Shivakumar et al, 1995); it has been suggested that the moderate elevation in wt p53 seen after DNA damage induces PCNA to cope with its DNA repair activities (Shivakumar et al, 1995); this inhibition in DNA replication but stimulation in repair by p53 might be accomplished by an independent pathway involving induction of p21 (El-Deiry et al, 1993) which interacts with PCNA protein auxiliary to DNA polymerase δ to inhibit the replication but not the repair functions of PCNA (Li et al, 1994). The bax gene which induces apoptosis (Figure 21) is upregulated by p53 whereas the bcl-2 gene which inhibits apoptosis in B cells is down-regulated by p53 (Miyashita et al, 1994a,b; Miyashita and Reed, 1995). Initiated cancer cells may lead to tumor development only when a 55 dysfunction in their apoptotic pathway takes place; some of the mechanisms leading to inactivation of the apoptotic pathway in cancer cells may result from an up-regulation in the bcl-2 gene (a Bcl-2 chimeric factor is produced in leukemias as a result of a translocation) or downregulation of the bax gene. Gene therapy for cancer could involve restoration of the apoptotic pathway in cancer cells leading to their suicidal death (see below). Figure 21. Involvement of Bax and Bcl-2 proteins in apoptosis. Bax is a potent inducer of apoptosis; binding of Bcl-2 to Bax (also binding of the E1B 19 kDa protein of adenovirus to Bax) prevents Bax from its apoptotic functions. From Boulikas T (1997) Gene therapy of prostate cancer: p53, suicidal genes, and other targets. Anticancer Res 17, 1471-1506. With the kind permission of Anticancer Research. Binding sites for p53 have been found at the origin of replication of polyomavirus with an inhibitory effect on virus replication in vitro (Miller et al, 1995) and at the SV40 ORI (Bargonetti et al, 1991) as well as in putative cellular origins of replication (Kern et al, 1991). A number of genes not containing p53 response elements may be repressed by p53 (Ginsberg et al, 1991; Mercer et al, 1991; Shiio et al, 1992; Seto et al, 1992).
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Gene Ther Mol Biol Vol 1, 1-172. Ma
Page 3 and 4: I. Introduction Monumental progress
Page 5 and 6: The use of retroviral vectors in hu
Page 7 and 8: displaying the cleavable EGF domain
Page 9 and 10: molecules in the nucleus (Lowe and
Page 11 and 12: sensitive mutations which allow pro
Page 13 and 14: processed as described in panel A s
Page 15 and 16: On the contrary, the payload capaci
Page 17 and 18: in K562 human erythroleukemia cells
Page 19 and 20: defective HSV virus (DeLuca and Sch
Page 21 and 22: complex into the cytosol from the e
Page 23 and 24: Gene Therapy and Molecular Biology
Page 25 and 26: delivered by Sendai virus-liposome
Page 27 and 28: plasmids with the cell surface, tra
Page 29 and 30: infected by adenovirus alone; infec
Page 33 and 34: B. Transcription factor binding sit
Page 35 and 36: A closely related family of ubiquit
Page 37 and 38: cells. I-CreI is a member of this c
Page 41 and 42: C. Considerations of chromatin stru
Page 45 and 46: A. The molecular basis of cancer im
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Page 49 and 50: ecombinant vaccinia virus expressin
Page 51 and 52: HIV-1 envelope DNA construct develo
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Page 57 and 58: Prives, 1994). Whereas the wild-typ
Page 59 and 60: mutant p53 (mutations on p53 are wi
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Page 63 and 64: Work from several groups has shown
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Page 67 and 68: Figure 23. A pathway leading to the
Page 69 and 70: Excessive necrotic death in cells o
Page 71 and 72: implantation, and similar processes
Page 73 and 74: normal cells in the surroundings. T
Page 79 and 80: A bicistronic retroviral vector (Ha
Page 81 and 82: C. Antisense ras gene transfer for
Page 83 and 84: equal to 6.0 showed S1 hyperreactiv
Page 85 and 86: protein (e.g. Smith et al, 1995; Fo
Page 87 and 88: transduced primary mouse fibroblast
Page 89 and 90: IL-1 - receptor antagonist protein
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Page 97 and 98: Isolation of an RNA aptamer that ca
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C. Transfer of other genes against
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Gene Therapy and Molecular Biology
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significant reduction in neointima
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(Prehn et al, 1996); this implies a
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B. Approaches to gene therapy of RA
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of human immunoglobulin and antigen
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A. Etiology and mechanisms of destr
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However, CsA also inhibits the acti
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The peptide kinin, after binding to
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intake when administered to adrenal
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Introgen Therapeutics (Austin and H
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When a subfragment of only 513 bp o
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Armentano D, Zabner J, Sacks C, Soo
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Brady HJM, Miles CG, Pennington DJ,
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Chen J, Stickles RJ, Daichendt KA (
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Day ML, Wu S, Basler JW (1993) Pros
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Farmer G, Bargonetti J, Zhu H, Frie
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Giovannangeli C, Perrouault L, Escu
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the neoplastic phenotype by replace
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integrate in a site-specific fashio
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Li R, Waga S, Hannon GJ, Beach D, S
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adiation-induced apoptosis in the g
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Nakaya T, Iwai S, Fujinaga K, Sato
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Polyak K, Xia Y, Zweier JL, Kinzler
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macrophages from simian immunodefic
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intimal hyperplasia in a rat caroti
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Trono D, Feinberg MB, Baltimore D (
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Wattiaux R, Jadot M, Warnier-Pirott
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similar to mammalian interleukin-1
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24. Gene Marking /Infectious Diseas
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Drug 50. Gene Therapy /Phase I /Can
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76. Gene Therapy /Phase I /Cancer /
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99. Gene Therapy /Phase II /Cancer
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120. Gene Therapy /Phase I /Monogen
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cancer not specified) /Immunotherap
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