Tumor suppression

By examining some of the over one thousand tumor-causing point mutations of p53 in the light of its structure, we can identify features of p53 that are necessary for tumor suppression. The amino acids most frequently changed in cancer cells are at or near the protein-DNA interface residues that are infrequently mutated, if at all, are in general far from the DNA-binding site. 

Pestka S (2003) A dance between interferon-alpha/beta andp53 demonstrates collaborations in tumor suppression and antiviral activities. Cancer Cell 4 85-87... 

SB-505124, both of which target the TbRI kinase domain, are in preclinical use. An alternative approach to inhibiting TGF- 3 signaling is to focus on the tumor suppressive function of this pathway. Promising future treatments will focus on pathways that are activated when the TGF-P signaling tumor suppressor pathway is inactivated. Examples are inhibitors to wnt signaling, CDK4 activation and IL-6. 

Thymidylate synthase (TS) is the rate-limiting enzyme in the DNA synthetic pathway and the target for 5-FU and folate analogs (Figure 14.3). Compared to normal tissues, TS is often overexpressed in tumor cells, probably as a result of tumor suppression loss of function, gene amplification or other mechanisms. Acute induction of TS protein as well as stable amplification of TS-specific genes may be associated with resistance to fluoropyrimidine derivatives [118, 119], and an inverse correlation between tumor TS expression and clinical response was found [120-122]. 

Ito T, Yoshihara C, Hamada K, Koyama Y (2010) DNA/polyethyleneimine/hyaluronic acid small complex particles and tumor suppression in mice. Biomaterials 31 2912-2918... 

The answer is a. (Hardman, p 1302.) Cyclophosphamide, an alkylating agent, reacts with purine and pyrimidine bases of DNA to form bridges and dimers. These products interfere with DNA replication. 5-FU, methotrexate, and 6-thioguanine are anti metabolites, and the steroid prednisone has some tumor-suppressive effects. 

The combination of tyrphostins with cytotoxic drugs can be followed by immunotherapy in order to eliminate residual disease. Though such combinations have not yet been examined, the combination of AG 490 and IL-12 against IL-6 dependent multiple myeloma recently showed impressive tumor suppressive effects [54], suggesting that the general idea may indeed be correct. 

Z2. Zou, Z., Anisowicz, A., Hendrix, M., Thor, A., Neveu, M., Sheng, S., Rafidi, K., Seftor, E., and Sager, R., Maspin A serpin with tumor-suppressing activity in human mammary epithelial cells. Science 263, 526-529 (1994). 

Wesley UV, Tiwari S, Houghton AN (2004) Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cells. Int J Cancer 109(6) 855—866. 

Lowe, S. W. and C. J. Sheer, Tumor suppression by Ink4a-Arf progress and puzzles. Curr Opin Gena Dev, 2003, 13(1), 77-83. 

Zhang, Y., Y. Xiong, and W. G. Yarbrough, ARF promotes MDM2 degradation and stabilizes p53 ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell, 1998, 92(6), 725-34. 

Cantley, L.C., and Neel, B., 1999, New insights into tumor suppression PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/Akt pathway. Proc. Natl. Acad. Sci. 96 4240-4245. 

Di Ciistofano, A., Pesce, B., Cordon-Cardo, C., Pandolfi, P.P., 1998, Pten is essential for embryonic development and tumor suppression. Nat. Genet., 19 348-355. 

Kitabayashi I, Aikawa Y, Nguyen LA, Yokoyama A, Ohki M (2001) Activation of AMLl -mediated transcription by MOZ and inhibition by the MOZ-CBP hsion protein. EMBO J 20 7184-7196 Klochendler-Yeivin A, Yaniv M (2001) Chromatin modifiers and tumor suppression. Biochim Biophys Acta 155LMI-10... 

Nagata Y, et al. Peptides derived from a wild-type murine proto-oncogene c-erbB-2/HER2/neu can induce CTL and tumor suppression in syngeneic hosts. J Immunol 1997 159 1336. 

Klochendler-Yeivin, A., Fiette, L., Barra, J., Muchardt, C., Babinet, C., and Yaniv, M. (2000) The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression. EMBO Rep. 1, 500-506. 

Note that some enzymes have important roles in nontransformed cells and/or tumor-suppressive activities. See text for details and references. 

Choi PM, Tchou-Wong KM, Weinstein IB (1990) Overexpression of protein kinase C in HT29 colon cancer cells causes growth inhibition and tumor suppression. Mol Cell Biol 10 4650-4657... 

El-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993 75 817-825. 

Lebedeva S, Bagdasarova S, Tyler T, Mu X, Wilson DR, Gjerset RA. Tumor Suppression and Therapy Sensitization of Localized and Metastatic Breast Cancer by Adenovirus p53. Hum Gene Ther 2001 12 763-772. 

Figure 7.20 Examples of haptens for the creation of antibodies directed toward the 6-phosphor-ylserine tumor suppressive protein p53. ...

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