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DNA-Binding Proteins and DNA-Synthesizing Enzymes in Eukaryotes
Published in Lubomir S. Hnilica, Chromosomal Nonhistone Proteins, 2018
The mechanism of these proteins involving in DNA replication is not known. However, a detailed analysis of the interaction of the E. coli DNA binding protein with DNA polymerase II has suggested a model to account for these various observations. E. coli DNA binding protein interacts with E. coli DNA polymerase II to form a protein-protein complex in the absence of DNA. DNA-binding protein, when bound to DNA, retains its ability to interact with DNA polymerase II and to form a ternary complex between DNA-binding protein, DNA polymerase II, and DNA. Neither E. coli DNA polymerase I nor DNA polymerase III nor phage T4-induced DNA polymerase interacts with DNA-binding protein. Thus, it appears that the specific stimulation is due to complex formation. The stimulation rate and extent of synthesis seen when the DNA-binding protein is added can be explained by destabilizing the double helix of DNA template as well as by binding to the polymerase during DNA synthesis, such that the polymerase does not dissociate from the template during processing.
Regulation of Cell Functions
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The regulation of cellular functions by growth factors, hormones, and other mitogens is exerted frequently at the level of gene expression through modification of the specific activities of transcription factors.367-369 These factors are nuclear proteins involved in the control transcription initiation by DNA polymerase II through the recognition by them of specific DNA sequences. An enormous number of transcription factors have been isolated and characterized recently.370 Some of these factors are represented by the products of proto-oncogenes encoding nuclear proteins such as Fos and Jun, which form homo- or heterodimers through leucine zippers and recognize the AP-1 binding site.371-373 Other nuclear oncoproteins such as Myc, Myb, Ets, and Rel may also function as transcription factors. The specific activities of transcription factors are regulated by phosphorylation, glycosylation, and other posttranslational modifications.374 Examples of growth factor-regulated transcription factors are mentioned next and others are discussed in chapters dedicated to specific growth factors.
Novel therapeutic targets for cancer metastasis
Published in Expert Review of Anticancer Therapy, 2020
Konstantin Stoletov, Perrin H. Beatty, John D. Lewis
Fifteen of the 23 genes were identified as host factor enhancers of metastasis because when they were knocked out metastasis decreased. These enhancer genes represent novel metastatic blocking targets for therapeutic use. Only 4 of these 15 enhancer genes have been described previously as host factor regulators of metastasis: T-cell control of NK cells (Entpd1), platelet α-granule function (Nbeal2), phagocyte-derived oxygen radical generation (Cybb), and a chaperone for tumor-progression-proteins (Hsp90aa1) [75,76,78,86]. A mitochondria-targeted small molecule Hsp90 inhibitor called gamitrinib has shown some efficacy in pre-clinical metastatic tumor-mouse studies for inhibition of metastases of prostate cancer to abdominal lymph nodes and liver [76]. The Hsp90 inhibitor triggered the loss of mitochondrial inner membrane potential which caused acute mitochondrial dysfunction in the tumor cells [76]. Other studies that use gamitrinib and doxorubicin, an anthracycline antibiotic that inhibits DNA polymerase II, as a combined treatment in prostate and breast cancer in vivo xenograft models showed significantly reduced tumor growth with no increase in cardiotoxicity from doxorubicin [87]. The cytotoxicity of this combination therapy increased apoptosis by increasing the expression of the pro-apoptotic transcription factor C/EBP-homologous protein and a stress kinase called c-Jun [87].