550: Cancer

Biochemistry 550 with Hayes at University of Wisconsin - Madison

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By: alexia augustine
Created: 2012-02-27
Size: 34 flashcards
Views: 9

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Ras

subfamily of GTPase involved in cell signaling for differentiation and growth. constitutive mutations in the ras gene can lead to uncontrolled growth

Ras

bio-molecular switches controlling cytoskeletal integrity, proliferation, differentiation, cell adhesion, apoptosis, and cell migration.
become proto-oncogenic through mutation

Tyrosine

residue in the active site that undergoes phosphorylation by bound ligand to activate insulin receptor

Bax

releases cytochrome C from the mitochondria when apoptosis occurs

T-loop in Cdks is...

phosphorylated to activate Cdk

Caspase 8

involved in 'Death Receptor Pathway' for cell apoptosis; initiator caspase
activated by FAS and TNFR1

Caspase 3

effector
final molecule involved in both 'Death Receptor' and 'Stress-induced' apoptosis pathway

Bcl

family of cell-death-related proteins
pro and anti apoptotic

Cyclin E

binds to G₁ phase Cdk2; phosphorylates p27 to inhibit Cyclin D and allow cell to progress to S-phase

Cyclin D is the over inhibitory cyclin that competitively binds to Cdk2
Cyclin E/Cdk2 mediates cell entry into S-phase
Cyclin A/Cdk2 mediates entry into G2-phase
Cyclin B/Cdk2 regulates entry into Mitotic cycle

What are the 5 areas of cell signalling key to understanding cancer?

cell cycle, cell death, DNA damage, Receptor, Signal transduction

Cdk

cyclin-dependent kinases
heterodimeric serine/threonine kinases help regulate cell-cycle progression, transciption and neuronal f(x)

Cdk2

important in first division during meiosis; mutation and loss of f(x) leads to sterility but otherwise normal development
cell cycle progression is not dependent on

Cdk4 and Cdk6

cell cycle progression is not dependent on
endocrine and hematopoietic development depend on proper f(x)

GEFs

Guanine Nucleotide Exchange Factors responsible for activation of small GTPases; when bound to GTPase accelerates disassociation of bound GDP to allow binding of GTP
opposes GAP

GAPs

GTPase activating proteins responsible for deactiv
ct antagonistically to inactivate GTPases by increasing their intrinsic rate of GTP hydrolysis. GDP remains bound to the inactive GTPase until a GEF binds and stimulates its release.

GEF stabilization...

destabilize the GTPase interaction with GDP and stabilize the nucleotide free GTPase until a GTP molecule binds to it

GTPase

active form is bound to GTP
inactive form is bound to GDP

Cycle between GAP and GEF

GTPase structure

2 loops (switch 1 & switch 2) situated on either side of bound nucleotide; switches + P-loop =Mg ion to increase affinity binding of nucleotide

GTPase mechanism

GEF changes conformation, opens binding site & (-) P-loop/switches interaction, (-)phosphate allows binding of new GTP; GEF sterically hinders magnesium-binding site & interferes w/ phosphate-binding region, base-binding region =accessible

Six Superpowers of Cancer

growth in the absence of 'go' signal; override of 'stop growth' commands; evasion of apoptosis; ability to stimulate blood vessel formation; infectious nature gives 'immortality'; ability to metastize

The Oncogene Theory

cancer = genetic basis; mutations in regulatory genes lead --> cancer; heritable mutations; virus can introduce oncogenes; chemical mutagenesis; understanding genetic basis could lead to treatments

Genetic Alterations

point mutations, gene amplifications, chromosomal translocations, insertions

Identifying Target Pathways

multiplex families affected; chromosomal marker maps to find correlation with oncogenic genes; determine oncogenic protein WT vs mutant f(x); experimental pathway map; based on map, describe oncogenic protein involvement

Understanding Pathways

cell cycle regulation, cell death, DNA damage response, receptor signaling, signal transduction

Hallmark of Cancer

Uncontrolled division; imbalance of cell death and proliferation

Cyclin B

1st cell regulator discovered; peak at entry into mitosis; expression of one protein band (cyclin B); binds with Cdk1

Analytic Detection Methods

supplementing fluorescent-labeled a.a. or sub-grps, sampling for electrophoresis; mutation of target sequence (what do you lose?);

Cyclins are...

[cyclin] regulated via synthesis and degradation (trascription/translation degradation => mitotic cyclin destruction box- MCDB); proteosome degrades; regulate Cdk by activating & using ATP to phosphorylate substrates;

Activation of Cdk by Cyclin

bind & change conf. => rxn w/GC helix "PSTAIR" that holds in Threonine regulating loop (T-loop); binding unwinds loop --> exposure, allows binding of ATP opposite of loop base; final activation step is phosphorylation of exposed Threonine161 (T-loop)

Cell Cycle Check points: G1 to S

checks for DNA damage, p53 recruited if damage detected, cycle stops via "cc-break" p21 (Cip1) for repair (through inhibition of Cdk2), Cdk2/CyclinE and Cdk4/CyclinD

Cell Cycle Check points: G2 to M

checks for completion of DNA replication, Cdk1/CyclinA tyrosine kinase activated via loss of phosphate on Tyr-15 (layered regulation)

Cyclin-Cdk pairs

CyclinD: Cdk4/6 [G1], CylcinE: Cdk2 [G1/S], CyclinA: Cdk 1/2 [S], CylcinB/Cdk1 [M]

About this deck

By: alexia augustine
Created: 2012-02-27
Size: 34 flashcards
Views: 9

About StudyBlue

“I have used this website for three exams, and I see a huge difference in my test results.”
Naj