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PDGF ( c-sis of Simian Sarcoma). Dermatofibrosarcoma. Simian Sarcoma Virus (SSV). SSV- transforming retrovirus found in the wooly monkey Transforming gene- v-sis Homolog in humans- first deemed c-sis, located on chromosome 22
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PDGF(c-sis of Simian Sarcoma) Dermatofibrosarcoma
Simian Sarcoma Virus (SSV) • SSV- transforming retrovirus found in the wooly monkey • Transforming gene- v-sis • Homolog in humans- first deemed c-sis, located on chromosome 22 • Sequencing of region indicated close similarities to the mitogen PDGF
PDGF Protein • PDGF is a family of proteins, and subunits A through D have been identified • This presentation concerned with A and B, but mostly PDGFB • Biologically active PDGF are homo and heterodimers; these dimers are assembled intracellularly
PDGF Protein • Control of biosynthesis/secretion occurs on several levels • Transcription • Post transcription • Proteolytic processing • Availability depends on association with extracellular matrix proteins
Biology of PDGFB • PDGFB is sufficient for mitogenesis • Different dimers stimulate different receptors- varies the cellular effect • Necessary for embyogenesis, while other subunits are not
Knockout Mice • Mice lacking the PDGFB gene are thus far identical to mice lacking PDGFRB • These knockouts die during late gestation from cardiovascular complications- issues ranging from glomeruli function in kidneys, to cardiac muscle malfunction • In embryos, highest expression is sprouting, immature, capillary endothelium and endothelium of growing arteries
PDGF Pathway • The dimerized PDGF ligands bind to cell surface receptor tyrosine kinases • These subsequently form homo or heterodimers of a and b subunits and auto-phosphorylate • Activated receptors interact with SH2 domains of several proteins and initiate many pathways • Including: PLCg, PI3K, SHP2 phosphatase, and Src family kinases • These converge on a set of immediate early genes
Firm, hyperpigmented dermal, subcutaneous nodules that grow slowly Most often found on trunk of body Commonly recur after standard surgery 30-40% of the time Uncontrolled division of fibroblasts Fibroblasts produce collagen 1A, and also contain PDGF receptors DFSP tissues express fusion protein COL1A1/PDGFB Dermatofibrosarcoma Protuberans (DFSP)
Fusion of Col1A1 Deregulates PDGFB • In DFSP tissue cells, often supernumerary rings and translocations are present which place the PDGFBgene under control of collagen 1 A promoter sequences • The resulting chimeric protein lacks the regulatory subunit of PDGFB, located in exon 1 of normal PDGFB • High levels of conservation occur in the PDGF segment of the chimeric protein, while COL1A1 sequences differ greatly across cell lines • Implications??
Karyotype of DFSP Cell Pedeutour et al. 1994
Chimeric Protein Wang et al, 1999
Future in DFSP • Diagnostic: Reverse transcriptase polymerase chain reaction (RT-PCR) detects COL1A1/PDGFB chimeric mRNA, and can be used to determine if a tumor is DFSP • Treatment: PDGF tyrosine kinase inhibitor has been suggested as drug therapy; ST1571 (imatinib) • Clinical trials still underway to test effectiveness, but much research is in progress