CELL CYCLE AND DIFFERENTIATION

Transcription

1 CELL CYCLE AND DIFFERENTIATION Dewajani Purnomosari Department of Histology and Cell Biology Faculty of Medicine Universitas Gadjah Mada

2 WHAT IS CELL CYCLE? 09/12/14 2

3 WHAT IS CELL CYCLE? cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication (replication). can be divided in two brief periods: interphase during which the cell grows, accumulating nutrients needed for mitosis and duplicating its DNA and the mitosis (M) phase, during which the cell splits itself into two distinct cells, often called "daughter cells". d.purnomosari@ugm.ac.id 3 09/12 /14

4 CELL DIVISION CYCLE Figure 17-1 Molecular Biology of the Cell ( Garland Science 2008) 09/12/14 d.purnomosari@ugm.ac.id 4

5 Figure 17-3 Molecular Biology of the Cell ( Garland Science 2008) Most cells must complete four tasks during the cell cycle, 1. grow, 2. replicate their DNA, 3. segregate their chromosomes into two identical sets and 4. divide. The complete process is typically divided into four phases 09/12/14 d.purnomosari@ugm.ac.id 5

6 CELL CYCLE The regulation of the cell cycle must ensure that the events in each phase is complete before moving to the next 09/12/14 6

7 HOW S THE CELL CYCLE REGULATE? 09/12/14 d.purnomosari@ugm.ac.id 7

8 CELL CYCLE REGULATORS Cyclin dependent kinase (CDK) CDKs consist only of a conserved catalytic kinase core of about 34 kda [Hanks and Hunter 1995], which is inactive by itself. throughout the cell cycle the concentration of these protein kinases remains 09/12/14 d.purnomosari@ugm.ac.id 8 constant.

9 CELL CYCLE REGULATORS Kinase activity requires association with regulatory subunits known as cyclins Cyclins have a periodic concentration rise and fall during the cell cycle 09/12/14 d.purnomosari@ugm.ac.id 9

10 CELL CYCLE REGULATORS Complete activation requires further phosphorylation at a conserved CDK threonine by the CDK-activating kinase, CAK 09/12/14 d.purnomosari@ugm.ac.id 10

11 CELL CYCLE REGULATORS The transfer of a phosphate group from ATP to the serine/threonine-hydroxyl group of target proteins which either gain or loose a function. Protein targets: cytoskeletal proteins, transcription factors, tumor suppresser genes and others [Nigg 1993]. 09/12/14 d.purnomosari@ugm.ac.id 11

12 CELL CYCLE REGULATORS Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase (Cdk) enzymes 09/12/14 d.purnomosari@ugm.ac.id 12

13 CYCLINS Cyclins are named cyclins because their appearance during the cell cycle is cyclical. The periodicity of cyclin is mediated by their synthesis and subsequent proteolysis degradation by ubiquitin/ proteasomes when their services are no longer required. 09/12/14 13

14 DIFFERENT CYCLIN-CDK DURING CELL CYCLE Different cyclins are present in different levels during different phases of the cell cycle The cyclins were named in the order in which they were discovered (similar case for cdk enzymes) 09/12/14 14

15 PAIRING OF CYCLINS WITH CYCLIN- DEPENDENT KINASES The D-type cyclins (D1, D2 and D3) bind CDK4 or CDK6 The E-type cyclins (E1 and E2) bind CDK2 The A-type cyclins (A1 and A2) bind CDK2 or CDC2 The B-type cyclins (B1 and B2) bind CDC2 09/12/14 15

16 ACTIONS OF CDK INHIBITORS, ANOTHER WAY OF REGULATING CELL CYCLE 09/12/14 16

17 09/12/14 17

18 WHAT KIND OF STIMULI AFFECTS THE CELL CYCLE? 09/12/14 18

19 THE CENTRAL GOVERNOR OF GROWTH AND PROLIFERATION All external signals related to cell growth and division must eventually regulate the activity of the CDKs. 09/12/14 19

20 CELL CYCLE PROPERTY There is a critical checkpoint in the mammalian cell cycle, called Restriction Point (R) Prior to R, the cell depends on external stimuli (growth factor) to progress through G1 After R, the cell become independent of external mitogenic stimuli and can complete the cell division cycle autonomously. 09/12/14 d.purnomosari@ugm.ac.id 20

21 CELL CYCLE PROPERTY 09/12/14 21

22 CELL CYCLE CHECKPOINTS 09/12/14 22

23 CONSEQUENCES OF LOSS OF CHECKPOINT CONTROLS Right: normal human karyotype, Left: deprived of Rad17 checkpoint protein resulting in endoreduplication 09/12/14 23

24 CONSEQUENCES OF LOSS OF CHECKPOINT CONTROLS 09/12/14 24

25 MITOSIS 09/12/14 25

26 09/12/14 26 Figure Molecular Biology of the Cell ( Garland Science 2008)

27 CYTOKINESIS 09/12/14 27 Figure Molecular Biology of the Cell ( Garland Science 2008)

28 MITOSIS AND MEIOSIS Figure 21-5 Molecular Biology of the Cell ( Garland Science 2008) 09/12/14 d.purnomosari@ugm.ac.id 28

29 WHICH CELLS UNDERGO CELL CYCLE? 09/12/14 29

30 STEM CELLS Many cells that lose their ability to divide as they mature tissues maintain stem cells to serve as a reservoir of undifferentiated cells Stem cells have the capacity to mature into many different cell types. 09/12/14 d.purnomosari@ugm.ac.id 30

31 STEM CELL HIERARCHY Nullipotency = terminal cell 09/12/14 d.purnomosari@ugm.ac.id 31

32 HEMATOPOIETIC AND MESENCHYMAL STEM CELL 09/12/14 32

33 CELL DIFFERENTIATION The process that a cell changes to carry out a specialized function Marked by: Morphology / Structure / Function d.purnomosari@ugm.ac.id /12 /14

34 /12 /14

35 CELL DIFFERENTIATION 1.The different cell types of a multicellular organism contain the same DNA. 2.A cell can change the expression of its genes in response to external signals. 3.Differences in mrna expression patterns among different cell types. 4.Different cell types synthesize different sets of proteins. 5.Gene expression can be regulated at many of the steps in the pathway from DNA to RNA to protein. d.purnomosari@ugm.ac.id 35 09/12 /14

36 WHAT FACTORS DETERMINING CELL DIFFERENTIATION? 09/12/14 36

37 TRANSCRIPTION FACTORS Signal from neighboring cell and Extracellular Matrix (ECM) proteins that regulate which genes are transcribed in a cell à essential to determining the pathway particular stem cells take as they differentiate. stem cells proliferate à undergo an asymmetric cell division à each of the two resulting daughter cells has its own unique life course Differentiate à mature Stem cell 09/12/14 d.purnomosari@ugm.ac.id 37

38 CELL DIFFERENTIATION 09/12/14 38

39 SUMMARY 09/12/14 39

40 CELL CYCLE highly ordered process that result in the duplication and transmission of genetic information from one cell generation to the next DNA must be replicated accurately The regulation of the cell cycle must ensure that the events in each phase is complete before moving to the next à check points are important 09/12/14 40

41 CELL CYCLE CHECKPOINTS 09/12/14 41

42 STEM CELL HIERARCHY 09/12/14 42

43 CELL CYCLE AND DIFFERENTIATION Dewajani Purnomosari Department of Histology and Cell Biology Faculty of Medicine Universitas Gadjah Mada