Cyclin Dependent Kinase1

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Cyclin Dependent KinaseCyclin Dependent Kinase

An introduction


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Protein KinaseProtein Kinase

y Change the activity of target protein by

adding phosphate group.

y Types of kinases

Serine/Threonine specific kinase.

Tyrosine specific kinase.

Histidine specific kinase.


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Cyclin Dependent KinaseCyclin Dependent Kinase

y A member ofSerine/threonine

specific kinase family.

y Activated by regulatory sub-unit known

as CYCLIN.

y 20Cdks and 25 Cyclins are identified by

HUMAN SEQUENCING.

y Still function of every cdks Not Fully

Identified.


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Types of CDKsTypes of CDKs

y CDK 1; Cyclin A, Cyclin B

y CDK 2; Cyclin A, Cyclin E

y CDK 3; Cyclin C ?

y CDK 4; Cyclin D(1-3)

y

CDK 5; p35,p39y CDK 6; Cyclin D(1-3)

y CDK 7; Cyclin H

y CDK 8; Cyclin C

y CDK 9; Cyclin T(1,2a,2b),Cyclin K

y

CDK 10;y CDK 11; Cyclin L

y CDK 12; Cyclin L

y CDK 13; Cyclin L


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Phylogenetic Analysis of CDKsPhylogenetic Analysis of CDKs

Ref 1


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CdkCdk StructureStructure

y PSTAIRE helix: alpha helix in the amino-terminal lobe of Cdks(also known as the alpha helix), which interacts with cyclin and is moved

inward upon cyclin binding, resulting in reorientation of key active-site residues.

The name of this helix comes from its amino-acid sequence, which is

conserved among all major Cdks.

y T-loop: flexible loop adjacent to the active site of Cdks, named for thethreonine whose phosphorylation is required for maximal activity. Sometimes called

the activation loop.

y L12 helix: small alpha helix adjacent to the T-loop in the active site ofCdk2 (residues 147151), which changes structure to a beta strand upon cyclin

binding


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Ref 2


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activationse ments

Cdk2 with Cyclin A Ref 3


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PSTAIRE

helix

Ref 4


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Ref 5


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CDK7

CDK 7

Ref 6


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CDK9 with cyclin T1 andTAT Protein

Ref 7


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ATP

Cdk9

Cycli

Tat


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Ribbon diagram of the human

CDK10 (a) without ATP and (b) in complex

with ATP

ATP

Ref 8


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FUNCTION OF CDKSFUNCTION OF CDKS

y Cell Cycle Regulation

y Transcription

y Neuronal Function

y Cellular Differentiation

y Apoptosis


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Cell cycle RegulationCell cycle Regulation


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TranscriptionTranscription

y Cdks phosphorylate serine 5 residue of

RNA pol II at CTD (carboxyl terminal

domain)

y Cdk7/cyclin H is the part of the

transcription factor II H (TF II H)

y Cdk9/cyclin T forms the positive

transcription elongation factor-b (P-TEFb)y This complex add phosphorus at serine 2

residue of RNA pol II


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TranscriptionTranscription contdcontd..

y Cdk8/cyclin C complex work as

transcription repressor

y Cdk11/cyclin L also shows dual role in

transcription


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Neuronal FunctionNeuronal Function

y Cdk5 has an essential role in the centraland peripheral nervous system

y Cdk5 regulates the cyto-architecture of thedeveloping brain and neuronal migration in

mitotic neuronsy It also shows important function in

Cytoskeleton dynamics

Synaptic plasticity

Drug addiction Synaptic endocytosis

Neurotransmitter release


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Cellular differentiationCellular differentiation

y Cdk5 act as positive modulator of early

myogenesis

y Cdk9 induces the differentiation in tissues

y The degree of Cdk9 directly correlates

with the degree of differentiation of

primary neuroectodermal and

neuroblastoma tumor cells


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ApoptosisApoptosis

y Cdk2 and Cdk5 have been shows

different roles in induction and

suppression of apoptosis in different

tissues


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REGULATION OF CDKSREGULATION OF CDKS

y Transcription & translation of their

subunit.

y On the formation of CDK\CYCLIN

complex.

y By post translation modification

Phosphorylation by Wee 1 & Myt 1 enzyme at

thr 14 & thy 15 residue. Phosphorylation by CAK at thr 160 residue.


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REGULATION OF CDKSREGULATION OF CDKS

yBy NATURAL INHIBITOR like

Cip/Kip inhibitorp21,p27,p57

INK4 inhibitor p15,p16,p18 andp19.


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SYNTHETIC INHIBITOR OF CDKSSYNTHETIC INHIBITOR OF CDKS

y Broad Cdk inhibitors : Flavopiridol

y Specific Cdk inhibitors : Roscovitine

y

Multiple Target inhibitors : compoundtargeting Cdks as well as additional

kinases such as VEGFR or PDGER.


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ROLEOF

ROL

EOF

CDK

SCDK

SIN

IN

DISEASEDISEASE


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MalariaMalaria

y Several Cdks have been characterized

from the genome of Malaria-causing

protozoan Plasmodium falciparum

y Pfmrkis homologs to human Cdk7 and

acting as CAK(cdk activator kinase) in

malarial parasite cell cycle.

y So it is most suitable target of the drugresistance parasite


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CancerCancer

y Failure of Cdks regulation leads high rate

of its activity which may be caused the

high cell proliferation and fail of cell cycle

regulation

y Due to this cell escape from different

check point like G1 & G2

y This leads the cell became cancerous


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CancerCancer contdcontd..

Overexpression of

cyclin B1

Hyperactivation ofCdk1

Tumorlike breast, colonandprostate


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Inactivation ofCip/kip protein

Overexpression ofcyclin E and/orcyclin A

Deregulation of

Cdk2

Ovariancarcinoma

Lung carcinoma

CancerCancer countdcountd


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Neurological DisordersNeurological Disorders

y Deregulation of cdk5 may be involved in

the pathogenesis of several

neurodegenerative disorders like :

Alzheimer`s disease

Parkinson`s disease

Traumatic brain injury


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Other diseasesOther diseases

y Type 2 Diabetes

Cdk5 prevent insulin secretion by pancreatic

cells and its inhibition glucose-dependent

secretiony Viral infection

Cellular cdks are also involved in replication

of some viruses(CMV,HPV,HIV) use cellular

cdks (cdk2,cdk9) for their transcription.


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Cyclin Dependent kinaseCyclin Dependent kinase

Inhibitors in clinical trailsInhibitors in clinical trails


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References

1. Malumbres M. and M.Barbacid, Mammalian Cyclin-dependent kinases.

Trends Biochem Sci,2005.30(11):P.630-41.2. Book The Cell-Cycle Control System Chapter 3, New Science

Press Ltd 2007 p(31-32)

3. De Bondt, H.L. et al.:Crystal structure of cyclin dependent kinase 2.

Nature1993,363:595602..

4. Philip J. Daya et al.:Crystal structure of human CDK4 in complexwith a D-type cyclin. PNAS March 17, 2009 vol. 106:p(41664170).

5. Mapelli M. The Structural Perspective on CDK5the Nero sci.

6. Lolli G.The Crystal Structure ofHuman CDK7 andIts ProteinRecognition Properties Structure, Vol. 12, 20672079, November,

2004

7. Tahir H. TahirovCrystal structure ofHIV-1Tat complexedwithhuman P-TEFb. Vol 46510 June 2010doi:10.1038/nature09131

8. Molscript (Kraulis,1991) and Raster3D (Merritt et al., 1997).

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Cyclin Dependent Kinase1