KRAS Kirsten RAS Mira Han Pedro Alves What

What is K-RAS? • A kind of guanine nucleotide (GTP/GDP) binding protein with intrinsic

What does K-RAS do? • function in the transduction of signals that control cell

MAPK signaling pathway • http: //www. reactome. org/cgibin/search? QUERY_CLASS=Database. Ide ntifier&QUERY=Uni. Prot: P 01116

Oncogene Protein p 21 (RAS) • Transforming protein encoded by ras oncogenes. Point mutations

Pathology related with KRAS • germline KRAS mutations in – Noonan syndrome – cardio-facio-cutaneous

Proto-oncogene • Normal gene that can become an oncogene throught –Mutation, or –Increased expression

K-RAS • K-RAS is the form (of RAS) found most often mutated in cancer

Possible Treatment • Blocking RAS isoprenylation – Isoprenylation is the addition of hydrophobic molecules

Farnesyltransferase inhibitors (FTI’s) • Farnesyltransferase (FFTase) – transferring a farnesyl group from farnesyl pyrophosphate

What was learned • FFTase inhibitors had preclinical successes • Inhibition of farnesylation of

Why K-RAS? • 6. 2 million people died from cancer 2000. • About 12

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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.

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 nucleotideexchange factor (GEF) and inactivated by a GTPase- activating protein (GAP).

MAPK signaling pathway • http: //www. reactome. org/cgibin/search? QUERY_CLASS=Database. Ide ntifier&QUERY=Uni. Prot: P 01116 • http: //www. genome. ad. jp/dbgetbin/show_pathway? hsa 04010+3845 • http: //wwwermm. cbcu. cam. ac. uk/swf 001 wkg. swf

Oncogene Protein p 21 (RAS) • Transforming protein encoded by ras oncogenes. Point mutations in the cellular ras gene (c-ras) can also result in a mutant p 21 protein that can transform mammalian cells. Oncogene protein p 21(ras) has been directly implicated in human neoplasms, perhaps accounting for as much as 1520% of all human tumors. EC 3. 6. 1. -.

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

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

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

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

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

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

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.