Tumor suppresser genes

Vectors can be injected into the kidney at the location of choice or at multiple sites either beneath the capsule or into the renal parenchyma. The disadvantage of this technique is that the transgene expression is limited to renal tissue surrounding the needle track and the needle penetration per se can cause cell damage. This approach could be relevant for localized renal tumors where anti-angiogenic, pro-apoptotic, or tumor-suppressive genes could be injected. 

Manipulating the genetic material by injecting tumor-suppressing genes has been an alternative way in cancer treatment. The 3p FUS1 gene is a tumor suppressor... 

The strongest risk factors for breast cancer are female gender and increasing age. Additional risk factors include endocrine factors (e.g., early menarche, nulliparity, late age at first birth, hormone replacement therapy), genetic factors (e.g., personal and family history, mutations of tumor suppresser genes [BRCAl and BRCA2]), and environmental and lifestyle factors (e.g., radiation exposure). 

An 86-year-old man received intravenous Thorotrast to investigate a bullet wound to his shoulder in 1939. He presented in 1993 with jaundice, leading to liver failure and death. Autopsy showed four separate carcinomas a cholangiocarcinoma in the left lobe of the liver, a well-differentiated tubular carcinoma of the antrum of the stomach, an invasive squamous carcinoma of the lung, and a well-differentiated adenocarcinoma of the ampulla of Vater. There were multiple mutations in the p53 tumor suppression gene caused by chronic alpha-ray irradiation. 

FIGURE 5.6.4 The p53 tumor-suppression gene acts from within the cell nucleus to destroy or correct cells with mutations that lead to uncontrolled proliferation. The mechanisms involved can appear to he complex because of the multiple steps in the process. (Courtesy of EMD Chemicals Inc., Gihhstown, NJ.)... 

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]. 

Kim S, Chin K, Gray JW, Bishop JM (2004) A screen for genes that suppress loss of contact inhibition identification of 1NG4 as a candidate tumor suppressor gene in human cancer. Proc Natl Acad Sci USA 101 16251-16256... 

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. 

Bouvet M, Bold RJ, Lee J, et al. Adenovirus-mediated wild-type p53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer. AnnSurg Oncol 1998 5 681-688. 

Tumor suppressor genes are genes that, by their inactivation due to mutations or deletion, promote tumor formation. The proteins for which they code are known as tumor suppressor proteins. Many of the known tumor suppressor proteins have a suppressing and negatively regulating effect on processes that are either directly associated with regulation of cell division or influence this in an indirect way. Other, equally important functions of tumor suppressor proteins are in the areas of DNA repair and cell adhesion. Inactivation of tumor suppressor genes can have various consequences ... 

Central to the function of the p53 protein is its abUity, as a transcription activator, to specifically bind to corresponding cis elements in the promoter region of various genes and to activate their transcription. The importance of sequence-specific DNA binding for the tumor-suppressing function of p53 became clear when the crystal structure of the complex of p53 protein and a corresponding DNA element were resolved and this structure was compared with the spectrum of known mutations of p53 protein occurring in human tumors (Cho et al., 1994). 

Fig. 14.11. Model of the function of the p53 protein. The figure summarizes in a very simplified manner two important functions of the p53 protein, which are assumed to be of importance for the tumor-suppressive activity of p53. The p53 protein is activated by DNA damage and other signals and can either bring about a halt in the cell cycle or initiate apoptosis of the cell. Activation of apoptosis can also be triggered via pathways other than the bax gene. The figure does not take into consideration the many other biochemical functions of p53, which can also be linked to the two pathways shown.

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