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K-RAS ( Kirsten RAS )

K-RAS ( Kirsten RAS ). Mira Han, Pedro Alves. What is K-RAS?. A kind of guanine nucleotide (GTP/GDP) binding protein with intrinsic GTPase activity . Member of the RAS protein family. Size: 189 amino acids; 21656 Da Attached to the Internal side of plasma membrane by a lipid anchor.

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K-RAS ( Kirsten RAS )

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  1. K-RAS( Kirsten RAS ) Mira Han, Pedro Alves

  2. What is K-RAS? • A kind of guanine nucleotide (GTP/GDP) binding protein with intrinsic GTPase activity. • Member of the RAS protein family. • Size: 189 amino acids; 21656 Da • Attached to the Internal side of plasma membrane by a lipid anchor.

  3. What does K-RAS do? • function in the transduction of signals that control cell growth and differentiation • Binding of GTP activates RAS proteins, and subsequent hydrolysis of the bound GTP to GDP and phosphate inactivates signaling by these proteins • Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase- activating protein (GAP).

  4. MAPK signaling pathway • http://www.reactome.org/cgi-bin/search?QUERY_CLASS=DatabaseIdentifier&QUERY=UniProt:P01116 • http://www.genome.ad.jp/dbget-bin/show_pathway?hsa04010+3845 • http://www-ermm.cbcu.cam.ac.uk/swf001wkg.swf

  5. Oncogene Protein p21 (RAS) • Transforming protein encoded by ras oncogenes. Point mutations in the cellular ras gene (c-ras) can also result in a mutant p21 protein that can transform mammalian cells. Oncogene protein p21(ras) has been directly implicated in human neoplasms, perhaps accounting for as much as 15-20% of all human tumors. EC 3.6.1.-.

  6. Pathology related with KRAS •  germline KRAS mutations in • Noonan syndrome • cardio-facio-cutaneous syndrome •  somatic mutations • in lung carcinoma • in breast carcinoma • in pancreatic carcinoma • in gastric carcinoma • in acute myeloblastic leukemia

  7. Proto-oncogene Normal gene that can become an oncogene throught Mutation, or Increased expression Oncogene is a gene that increases the chance that a normal cell develops into a tumor cell

  8. K-RAS • K-RAS is the form (of RAS) found most often mutated in cancer • The mutant oncogene is hard to be differentiated by drugs since most of the times it only has one amino acid difference

  9. Possible Treatment • Blocking RAS isoprenylation • Isoprenylation is the addition of hydrophobic molecules to a protein to facilitate its attachment to the cell membrane

  10. Farnesyltransferase inhibitors (FTI’s) • Farnesyltransferase (FFTase) • transferring a farnesyl group from farnesyl pyrophosphate (FPP) to the pre-RAS protein (isoprenylation) • GGTase • FTIs and GTIs was tried • resulted in high toxicity

  11. What was learned • FFTase inhibitors had preclinical successes • Inhibition of farnesylation of a number of other proteins • FTIs, whilst not RAS specific, still have potential for cancer therapy

  12. Why K-RAS? • 6.2 million people died from cancer 2000. • About 12 million contracted malignant tumors in 2000. • RAS is responsible for about 20% of all human tumors. • By learning about K-RAS we can learn about other pathways related to cancer.

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