Carcinogenesis and Neoplasia ... a Companion Site.

SRC genes

The SRC gene is a proto-oncogene that encodes a 60 kDa non-receptor tyrosine kinase, pp60c-src, and is the human homologue of v-Src, the transforming gene of Rous Sarcoma Virus. The cellular c-Src is linked to an array of signaling pathways impacting cellular proliferation, transformation, differentiation , survival, adhesion and migration. Overexpression and activation of c-Src is linked to the development of roughly 50% of human tumors derived from the colon, liver, lung, breast, and pancreas. Histone deacetylase (HDAC) inhibitors, which possess anti-cancer activity, repress SRC transcription in a wide variety of human cancer
cell lines.

The largest class of p-Tyr recognition domains are the family of SH2 domains that were first identified as conserved sequences in the oncoproteins Src and Fps. SH2 domains bind phosphorylated tyrosine residues in longer peptide motifs within a target proteins. SH2 domains recognize phosphotyrosine residues and SH3 domains recognise proline-rich sequences. Similar SH2 domain sequences occur in signal transduction intracellular proteins, such as Abl, ZAP70, STAT proteins, Grb2, and RasGAP.

The SRC gene is regulated by at least two promoters each of which is associated with its own distinct exon. Differential promoter usage and subsequent splicing to a common downstream exon generates Src transcripts that possess identical coding capacity yet have different 5' noncoding regions.

The SRC1α (SRC1A) promoter appears to regulate expression in many tissues, and is regulated by the Sp1 family of transcription factors. The proximal SRC1α promoter displays many hallmarks of a housekeeping gene including high GC content, in polypurine:polypyrimidine sequences (TC1, TC2 and TC3), together with multiple start sites. The factor hnRNP-K binds to the Pu:Py sequences and modulates transcriptional activity of the SRC1α promoter.

The distal SRC1α promoter is located upstream of the SRC1α promoter, is controlled by Hepatic Nuclear Factor (HNF-1), and is expressed in a much more restricted fashion than is the proximal promoter. HNF-1 is a homeodomain containing transcription factor that regulates various genes intestine and liver, so may be an important factor in regulating overexpression of SRC in malignancies that originate in these tissues.



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