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