Bunn cyklus principy regulace bunnho rstu a bunnho
Buněčný cyklus - principy regulace buněčného růstu a buněčného dělění
Mitóza Dr. B. Duronio, The University of North Carolina at Chapel Hill
Průběh mitózy v buněčné kultuře fibroblastů Dr. B. Duronio, The University of North Carolina at Chapel Hill
Buněčný cyklus Dr. B. Duronio, The University of North Carolina at Chapel Hill
Kinázy závislé na cyklinech kontrolují buněčný cyklus Dr. B. Duronio, The University of North Carolina at Chapel Hill
Kontrola vstupu do mitózy - výsledek využití různých buněčných modelů
Experimental Systems Important for Cell Cycle Studies Saccharomyces cerevisiae Schizosaccharomyces pombe Dr. B. Duronio, The University of North Carolina at Chapel Hill Arbacia punctulata Xenopus laevis
Cyclin was Discovered in Sea Urchin Embryos can stimulate to lay lots of eggs Protein Level cyclin A cyclin B Time M Dr. B. Duronio, The University of North Carolina at Chapel Hill M M
Frog life cycle OOCYTE GROWS WITHOUT DIVIDING (MONTHS) FERTILIZATION FERTILIZED EGG DIVIDES WITHOUT GROWING (HOURS) 1 mm sperm tadpole feeds, grows and becomes an adult frog
The Maturation of Frog Eggs An Assay for Maturation Promoting Factor (MPF) Yoshio Masui, 1971
MPF Activity Peaks Before Each Cell Division Moreover, MPF has kinase activity
Dr. B. Duronio, The University of North Carolina at Chapel Hill
Dr. B. Duronio, The University of North Carolina at Chapel Hill Purification of MPF: The Birth of Cyclin Dependent Kinases This is cdc 2+!! (Cdc 28 in S. cerevisiae) This is cyclin!! Which = cdc 13+ in S. pombe
Fission yeast: Schizosaccharomyces pombe Dr. B. Duronio, The University of North Carolina at Chapel Hill
Budding Yeast Saccharomyces cerevisiae Dr. B. Duronio, The University of North Carolina at Chapel Hill
Cdc Mutants Arrest at the Same Cell Cycle Phase Permissive (low) temperature Dr. B. Duronio, The University of North Carolina at Chapel Hill Restrictive (high) temperature
Cdc Genes Encode Proteins Needed for the G 2 -M Transition: Studies in S. pombe cdc 2+ encodes a kinase Moreover = cdc 28 in S. cerevisiae! Dr. B. Duronio, The University of North Carolina at Chapel Hill
Phosphorylation of CDK Targets Changes Their Activity Now performs a cell cycle function Dr. B. Duronio, The University of North Carolina at Chapel Hill
Jak jsou CDK regulovány? 1. prostřednictvím syntézy a odbourávání cyklinů 2. fosforylací 3. pomocí CDK inhibitory proteins (CKIs)
Cyclin Destruction is Controlled by Ubiquitination Dr. B. Duronio, The University of North Carolina at Chapel Hill
Představují cykliny jediný způsob regulace CDK?
Exprese cyklinů v jednotlivých fázích BC Dr. B. Duronio, The University of North Carolina at Chapel Hill
CDK jsou regulovány fosforylací
Conformational Changes Associated with CDK Phosphorylation Free CDK The T-loop blocks substrate access CDK + Cyclin T 161 phosphorylation Binding of cyclin Phosporylation moves the T-loop more
Cyclin Dependent Kinase Inhibitors (CKIs)
Dr. B. Duronio, The University of North Carolina at Chapel Hill The p 21 Family of CDK inhibitors (p 21 CIP 1/WAF 1, p 27 KIP 1, p 57 KIP 2) active CDK Cyclin inactive + p 21 CDK p 21 Cyclin p 27 Ki p 1 Cyclin A CDK 2 Jeffrey et al. (1995) Nature 376: 313 CDK 2 Cyclin A Russo et al. (1996) Nature 382: 325
Dr. B. Duronio, The University of North Carolina at Chapel Hill The INK 4 Family of CDK inhibitors INK 4 a INK 4 b INK 4 c INK 4 d (p 16 , p 15 , p 18 , p 19 ) active CDK 4/6 Cyclin D inactive + INK 4 Russo et al. (1998) Nature 395: 237 Brotherton et al. (1998) Nature 395: 244 CDK 4/6 Cyclin D INK 4 +
CKIs Regulate the G 1 -S Transition (p 16) (p 21, p 27) Dr. B. Duronio, The University of North Carolina at Chapel Hill
Nature Reviews Cancer 2001, 1: 222
Dr. B. Duronio, The University of North Carolina at Chapel Hill
p. RB Binds to the E 2 F Transcription Factor Dr. B. Duronio, The University of North Carolina at Chapel Hill
G 1 Cyclin CDKs Phosphorylate p. RB Dr. B. Duronio, The University of North Carolina at Chapel Hill
Proliferation Signals p 16 Regulates p. RB Phosphorylation Dr. B. Duronio, The University of North Carolina at Chapel Hill
Nature Reviews Cancer 2001, 1: 222
Kontrola buněčného cyklu úzce souvisí s: 4 kontrolou buněčného růstu; 4 přítomností růstových faktorů a dalších růstových stimulů a živin; 4 působením ostatních buněk populace a mezibuněčné hmoty.
The Difference Between Growth and Cell Division Growth with No Cell Division No Growth Cell Division + Growth = Proliferation!
Growth with No Cell Division: A Differentiated Neuron Dr. B. Duronio, The University of North Carolina at Chapel Hill
Cell Division with No Growth: Early Development 1 mm sperm Dr. B. Duronio, The University of North Carolina at Chapel Hill
Nature Reviews Cancer 2001, 1: 222
Growth Factors Induce Cell Cycle Progression Growth Factors act at the Restriction Point Dr. B. Duronio, The University of North Carolina at Chapel Hill
Nature Reviews Cancer 2001, 1: 222
Dr. B. Duronio, The University of North Carolina at Chapel Hill pm = post mitotic ps = pre-synthetic Zetterberg and Larsson, PNAS 82: 5365 (1985)
Growth Factors Induce Gene Expression Dr. B. Duronio, The University of North Carolina at Chapel Hill
Growth Factors Induce Cyclin D 1 Expression Sherr and Mc. Cormick, Cancer Cell, Vol 2, 103 -112 (2002)
Mitogen Induced Cell Cycle Progression in Cell Culture Dr. B. Duronio, The University of North Carolina at Chapel Hill
Cell Cycle Checkpoints
Cell Cycle Checkpoints Improve Cell Viability Weinert and Hartwell, Science 246: 629 (1989)
How do Cell Cycle Checkpoints Work? Zhou and Elledge Nature 408, 433 - 439 (2000)
Zhou and Elledge Nature 408, 433 - 439 (2000)
Signal Sensor Transducer Effector Dr. B. Duronio, The University of North Carolina at Chapel Hill
Dr. B. Duronio, The University of North Carolina at Chapel Hill
Metaphase in a mammalian cell
The Metaphase to Anaphase Transition
The Spindle Assembly Checkpoint
poškození DNA poruchy buň. cyklu poruchy buň. dělení nedostatek živin a růstových faktorů kontaktní inhibice vliv ECM zástava buň. cyklu (restriction point, checkpoints) setrvání v G 0 fázi apoptóza dostatek živin a růstových faktorů mitogeny proliferace
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