Cancer Flashcards
Conversion
Proto oncogene into oncogene as gain of function mutation
- pt mutation in proto oncogene results in constitutively acting proteing product
- localized reduplication (gene amplification) of DNA segment that includes proto oncogene, leading to over expression of encoded protein
- chrom translocation brings growth reg gene under control of diff promoter & that cause inappropriate expression of gene.
Activating mutations or overexpression of EGF R can transform cells
- Pt mutation alters single aa (val to glutamine) in transmem region of Her2 R causes dimerization of 2 R proteins w/o normal ligand
- Protein constitutively active as kinase
- del that causes loss of extracell ligand binding domain in R leads to constitutive activation of protein kinase
Human breast cancers
over express Her2 R
Low EGF concentration can cause cell stimulation & proliferation!
20-25% of all breast cancers are HER2+
Signal Transduction protein Ras
After EGF binding to RTK (tyrosine kinase R)
Adapter prot GRB2 binds to specific phosphotyrosine on RTK & to Sos which interacts w/ inactive Ras-GDP
GEF activity of Sos promots formation of active RasGTP
Ras anchored to membrane
Beyond Ras
Steps involving Ras bidnign to Raf
Then Raf binds to & phosphorylates MEK
MEK then activates MAP kinase
MAP Kinase phosphorylates many diff proteins
Constitutively active signal transduction proteins
Ras proto oncogene can become oncogene by substitution of any aa for glycine in position 12
This reduces Ras GTPase activity
Alters structure of Ras
Get oncoprotein
Constitutively active Ras oncoproteins expressed in many regions!
c-Src
Encodes a constitutively active cytosolic protein tyrosine kinase src
Normally inactive by phosphorylation of tyrosine reside @ 527
Hydrolysis of phosphotyrosine 527 by a phosphatase activates c-Src
Tyrosine 527 is missing/altered in Src oncoproteins that cave constitutive kinase activity
In Rous sarcoma virus, src gene has deletion that eliminates cSrc amino acids thus Src kinase is always active.
c-myc
Burkitt’s lymphoma
c myc gene translocated to site near heavy chain antibody genes
In juxtaposition w/ ehancer of antibody genes
Translocated myc gene now regulated by antibody enhancer is continually expressed causing B cell to become cancerous
Duplication of seg of DNA w/ myc gene HIGH expression of otherwise normal myc protein
Follicular lymphoma w/ bcl2
Translocation of 14:18 fuses transcriptional enhancer element of gene on chrom 14, that makes 1 protein subunit of an antibody to transcription unit of a gene, on chrom 18, that encodes Bcl2 (- regulator of apoptosis)
Bcl2 protein is produced in antibody producing cells, blocking any self destruction signals from inducing apoptosis in those cells.
loss of p16 and RB tumor suppressor genes
or
overexpression of cyclins
over expression of cyclin D1 (proto oncogene product) or loss of tumor suppressor genes of p16 & Rb can cause inappropriate unreg passage
Restriction of late G1
Tumors
enhance glycolysis & suppress oxidative phosphorylation
High rates of nucleotide, fatty acid & protein syn
Purine ring
Gly (N7)
Asp (N1)
Gln (N3 & N9)
make up purine ring
PPP
control of PPP in normal cells by activating p53 by DNA damage
use TIGAR (apoptosis regulator) & PGM (mutase)
This generates NADPH (reducing power) & ribose 5 phosphate for nt syn & DNA repair
Control of PPP in tumors
tumors express pyruvate kinase M2 & TKTL1
PK-M2 allows glycolytic intermeds to accumulate & TKTL1 can catalyze nonox PPP & suppress ox flux
Mismatch b/t amt of R5P & NADPH!
TCA interaction
Need to get rid of NADH so glycoslysis keeps moving & generating NAPDH so fatty acid & nt syn keep going
Tumor cells get NADPH from malic enzyme
Glutamine is essential for process!
R5P accumulate
Pyruvate kinase M2 is slow enzyme! Responsible for increase in nonox PPP flux in tumors.
