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The Rous Sarcoma Virus Oncogene and its Proto-Oncogene Counterpart
Published in Pimentel Enrique, Oncogenes, 2020
In spite of numerous studies the mechanisms responsible for the phenotypic transformation of cells induced by the v-src oncogene product remain unknown. However, some clues to the solution of this complex problem have been obtained by the results of experiments performed in the last few years.
Protein Phosphorylation
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The functional properties of Src proteins partially depend on their state of phosphorylation. In comparison to the v-Src oncoprotein, the normal c-Src protein is characterized by a lower level of tyrosine kinase activity. The major sites of phosphorylation are partially different for the viral and cellular Src proteins: in v-Src the sites are Ser-17 and Tyr-416 and in c-Src are Ser-17 and Tyr-527. The Ser-17 site is phosphorylated by cAMP-dependent kinase and Tyr-527 is phosphorylated by an independent cellular tyrosine kinase.113 Phosphorylation at Ser-17 is a cell cycle-associated event, but it does not affect the Src functional properties in CEF cells.114,115 Overexpressed c-Src protein is phosphorylated at Tyr-416 and exhibits increased kinase activity when isolated from cells incubated with orthovanadate, a protein tyrosine phosphatase inhibitor.116 Analysis of c-Src protein mutants containing a phenylalanine substitution for tyrosine at position 416 indicates that phosphorylation of Tyr-416 has a positive regulatory effect on the biological activity of the protein, but this effect does not directly correlate with a general effect on the total level of tyrosine kinase activity in vitro or the level of tyrosine phosphorylation of cellular proteins in vivo.117
Molecular Biology of Lung Cancer as the Basis for Targeted Therapy
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
Oliver Gautschi, Philip C. Mack, Jim Heighway, Paul H. Gumerlock, David R. Gandara
Proto-oncogenes are genes that contribute to malignant transformation when mutationally activated or overexpressed. In 1917, Rous reported that sarcoma in chickens could be caused by a transmissible agent. This observation led to the discovery of the Rous sarcoma virus and the subsequent isolation of v-Src, the transforming component of the viral genome and the first known oncogene. A human gene with homology to v-Src (SRC) was subsequently identified, and in 1980 Hunter and Sefton found that v-Src encodes a mutant kinase, which is constitutively active, thereby transforming cells (4). These and other studies demonstrated that a range of viral oncogenes had related normal counterparts in mammalian genomes. In view of the potential for such sequences to cause malignancy when misregulated, they were termed proto-oncogenes. The human homologue SRC was initially thought to be a relatively weak protooncogene, but recent data indicate that SRC kinase is an important regulator of migration, proliferation, survival, angiogenesis, and inflammation in normal and cancer cells (5). Potential clinical implications of these findings in lung cancer are now being explored in clinical trials with small molecule inhibitors of SRC kinase (6).
Genistein Suppresses v-Src-Driven Proliferative Activity by Arresting the Cell-Cycle at G2/M through Increasing p21 Level in Src-Activated Human Gallbladder Carcinoma cells
Published in Nutrition and Cancer, 2021
Misaki Ono, Mikako Takeshima, Asuka Nishi, Takako Higuchi, Shuji Nakano
HAG-1 is a human epithelial cell line derived from a moderately differentiated adenocarcinoma of the gallbladder (22). HAG/neo3-5 cells were obtained by transfection of HAG-1 cells with plasmid pSV2neo alone, which carries the gene for neomycin resistance, and used as a vehicle control. HAG/src3-1 cells that express p60v-src protein were obtained by co-transfection of the pSV2/v-src, along with pSV2neo (7). v-Src has a constitutively activated tyrosine kinase activity by the lack of negative regulatory domain. Cells were cultured in Dulbecco’s minimum essential medium (Wako, Osaka, Japan) supplemented with 10% fetal bovine serum (Life Technologies, Carlsbad, CA, USA), 100 IU/ml penicillin, and 100 µg/ml streptomycin in a humidified atmosphere of 95% air and 5% CO2 at 37 °C. To purify the clonal populations, HAG/src3-1 and HAG/neo3-5 cells were grown for 14 day in the culture medium containing G418 (200 µg/ml) before experiments. Genistein, daidzein, glycitein and equol (more than 98.0% of purity) were purchased from Sigma-Aldrich (St. Louis, MO, USA) and stored at −20 °C. A 100 mM solution was prepared by dissolving the components with dimethyl sulfoxide (DMSO, Sigma-Aldrich) immediately before experimental use. The final concentration of DMSO was adjusted to 0.01%, which was confirmed to be non-cytotoxic for at least 72 h exposure.
Role of co- and post-translational modifications of SFKs in their kinase activation
Published in Journal of Drug Targeting, 2020
Mei-Lian Cai, Meng-Yan Wang, Cong-Hui Zhang, Jun-Xia Wang, Hong Liu, Hong-Wei He, Wu-Li Zhao, Gui-Ming Xia, Rong-Guang Shao
The Src family kinases (SFKs) are the largest family of non-receptor tyrosine kinases and are involved in a variety of pathways to regulate proliferation, angiogenesis, invasion and metastasis. The SFKs have nine members: LYN, FYN, LCK, HCK, FGR, BLK, FRK, YES and SRC. Some SFKs (Src, Fyn, Frk and Yes) are expressed in most cell lines, but the others are expressed in specific cell types: Lyn in haematopoietic cells, Lck in T lymphocytes, Hck in myeloid cells, Blk in B cells, and Fgr in myeloid cells and B cells [1]. The origins of SFKs can be traced back to a study by Peyton Rous. In 1911, he first described a virus that could induce solid tumours in birds [2]. In the 1970s, studies of the Rous sarcoma virus identified v-Src as the viral oncogene responsible for cellular transformation [3]. Shortly thereafter, investigators found that v-Src originated from a cellular progenitor, the proto-oncogene c-Src [4]. After these reports, extensive data on the function and mechanism of action of Src and the other SFKs members were successively reported. Among these family members, Src is the most widely studied. This kinase plays significant roles in regulating signal transduction and tumorigenesis [5]. For example, Src was found to be overexpressed with increased activity in numerous human malignancies, such as breast cancer [6], colon cancer [7], glioblastoma tumours [8], and so on. Further studies showed that after Src was activated, an array of signalling networks associated with proliferation and metastasis could be provoked persistently, such as PI3K-AKT [9], Ras-MEK-ERK [10], STAT3-c-Myc [11], β-catenin and so on, to initiate growth and invasion.