REGULATION OF CELL CYCLE BY PROTEIN KINASES by steepslope9876

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									REGULATION OF CELL
 CYCLE BY PROTEIN
     KINASES
 BIOL 306 -BIOCHEMISTRY II
       H.ESRA AKGÜL
          01040604
        References:
LEHNINGER PRINCIPLES OF
BIOCHEMISTRY
www.biop.ox.ac.uk
www.biochemj.org
         SUBJECTS:

AN INTRODUCTION
CELL CYCLE
IMPORTANCE OF PROTEIN KINASES
LEVELS OF CYCLIN DEPENDENT
PROTEIN KINASES OSCILLATES
CRITICAL PROTEINS IN CDKs
REGULATE
Cell division requires a ordered sequence
of biochemical events that assures every
daughter cell a full complement of
molecules required for life.
Control of cell division in eukaryotic cells
have revealed regulatory mechanisms.
Protein kinases and protein
phosphorylation are central to the timing
mechanism that determines entry into cell
division and ensures orderly passage
through
Cell cycle
                   Phases:

S PHASE:DNA is replicated to produce copies
for both daughter cells.
G2 PHASE:New proteins are synthesize and the
cell double in size
M PHASE: (MITOTIC)maternal nuclear envelope
breaks down,paierde chromosome are pulled to
opposire of cell and cytokinesis ,producing two
daughter cell
G1 PHASE:The waiting period of again dividing.
G0 PHASE: Ceases phase,entering the
quiscent.If cell starts to divide,it reenters to G1 .
  IMPORTANCE OF PROTEIN
         KINASES
The timing of the cell cycle is controlled by
protein kinases with activities that change
in response to cellular signals.
By phosphorylating of proteins,protein
kinases the metabolic activities to produce
cell division.
          WHAT IS CDKs?

The kinases are heterodimers with a
regulatory subunit, cyclin, and a catalytic
subunit, cyclin-dependent protein
kinase (CDK). In the absenceof cyclin, the
catalytic subunit is virtually inactive.When
cyclin binds, the catalytic site opens up,
aresidue essential to catalysis becomes
accessible
Cdk2 structure:
CDK activities show striking oscillations
These oscillations are the result of four
  mechanisms for regulating CDK activity:
1-phosphorylation or dephosphorylation of the
  CDK,
2- controlled degradation of the cyclin subunit,
3-periodic synthesis of CDKs and cyclins,
4-the action of specific CDKinhibiting proteins.
           Regulation of CDks by
             phosphorylation
The activity of a CDK is strikingly affected by two critical
   residues in the protein
      Phosphorylation of Tyr15 near the amino
terminus renders CDK2 inactive; the P –Tyr residue is
in the ATP-binding site of the kinase, and the negatively
charged phosphate group blocks the entry of ATP. A
specific phosphatase dephosphorylates this P –Tyr
residue, permitting the binding of ATP.
     Phosphorylation of Thr160 in the “T loop” of CDK,
   forces the T loop out of the substrate binding cleft,
   permitting substrate binding and catalytic activity.
Controlled degradation of cyclin:

Progress through mitosis requires first the
activation then the destruction of cyclins A
and B, which activate the catalytic subunit
of the M-phase CDK. These cyclins
contain near their amino terminus the
sequence Arg–Thr–Ala–Leu–Gly–Asp–Ile–
Gly–Asn, the “destruction box,” which
targets them for degradation.The
DBRP(destruction box recognizing
protein.) recognize this protein.
Ubiquitin:Cyclin and activated ubiquitin are
 covalently joined by the enzyme ubiquitin
 ligase
Several more ubiquitin molecules are then
 appended, providing the signal for a
 proteolytic enzyme complex, or
 proteasome, to degrade cyclin.
      The feedback mechanism
   Increased CDK activity activates cyclin proteolysis.
   Newly synthesized cyclin associates with
and activates CDK, which phosphorylates and activates
DBRP. Active DBRP then causes proteolysis of cyclin.
  Lowered [cyclin] causes a decline in CDK activity, and
the activity of DBRP also drops through slow, constant
dephosphorylation and inactivation by a DBRP
   phosphatase.The cyclin level is ultimately restored by
   synthesisof new cyclin molecules.
Regulated Synthesis of CDKs
        and Cyclins
CyclinD, cyclin E, CDK2, and CDK4 are
synthesized only when a specific
transcription factor, E2F, is present in the
nucleus to activate transcription of their
genes. Synthesis of E2F is in turn
regulated by extracellular signals such as
growth factors and cytokines
         Inhibition of CDKs
  Specific protein inhibitors bind to and
  inactivate specific CDKs. One such protein
is p21.
Critical proteins:
How does the activity of CDK control
the cell cycle?
 BehindCDK regulation by inspecting the
  effect of CDKs on the structures of laminin
  and myosin and on the activity of
  retinoblastoma protein.
pRb; when DNA damage is detected, this
  protein participates in a mechanism that
  arrests cell division in G1
Breakdown of the nuclear envelope before
segregation of the sisterchromatids in mitosis is
partly due to the phosphorylationof laminin by a
CDK, which causes laminin filaments to
depolymerize.
After the division, CDK phosphorylates a small
regulatory subunit of myosin, causing
dissociation of myosin from actin filaments and
inactivating the contractile machinery
When pRb, is phosphorylated,itcannot bind and
inactivate EF2, a transcription factor that
promotes synthesis of enzymes essential to
DNA synthesis. If the regulatory protein p53 is
activated by ATM and ATR, protein kinases that
detect damaged DNA, it stimulates the synthesis
of p21, which can bind to and inhibit cyclin E–
CDK2 and thus prevent phosphorylation of pRb.
Unphosphorylated pRb binds and inactivates
E2F, blocking passage from G1 to S until the
DNA has been repaired.

								
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