Cell growth regulation Flashcards
What are mitogens?
Proteins that stimulate proliferation
what are paracrine proteins?
produced locally to stimulate proliferation of a different cell type that
has the appropriate cell surface receptor
What are autocrine proteins?
Produced by a cell that also expresses the appropriate cell surface receptor
What are endocrine proteins?
like conventional hormones, released systemically for distant effects
Steps involved in DNA replication?
- DNA is replicated semiconservatively (daughter cells
inherit one parental and one new strand) - New DNA is synthesized in the 5’ to 3’ direction from
deoxynucleotide triphosphate precursors at a
replication fork by a multienzyme complex (a
replication machine) - Fidelity is determined by base pairing (A=T, G≡C)
and presence of a proof reading enzyme in DNA
polymerase - Synthesis of the new DNA strand uses an RNA
primer and occurs continuously on the leading strand
and discontinuously on the trailing strand (giving rise
to Okazaki fragments, which are ligated together after
removal of the RNA primer)
What are the steps involved in mitosis?
- Prophase (1)
– Nucleus becomes less definite
– Microtubular spindle apparatus assembles
– Centrioles (yellow) migrate to poles - Prometaphase
– Nuclear membrane breaks down
– Kinetochores attach to spindle in nuclear region - Metaphase (2)
– Chromosomes (blue) align in equatorial plane - Anaphase (3)
– Chromatids separate and migrate to opposite poles - Telophase (4)
– Daughter nuclei form - Cytokinesis
– Division of cytoplasm
– Chromosomes decondense
What are examples of S-phase active drugs?
- 5-flurouracil
- Bromodeoxyuridine
What is 5-flurouracil?
an analogue of thymidine blocks thymidylate synthesis
What is bromodeoxyuridine?
another analogue that
may be incorporated into DNA and detected
by antibodies to identify cells that have
passed through the S-phase
What are examples of M-phase active drugs?
-Colchicine
-Vinca alkaloids
-Paclitaxel
What does colchicine do?
stabilizes free tubulin, preventing microtubule polymerization and
arresting cells in mitosis – used in karyotype analysis
What do vinca alkaloids do?
similar action to colchicine
What does paclitaxel do?
Taxol, stabilizes microtubules, preventing de-polymerization
What cell cycle drugs are used in cancer treatment?
5-Fluorouracil, paclitaxel, the vinca alkaloids and tamoxifen are used in treatment of cancer
What do cell cycle controls ensure?
Controls (involving specific protein kinases and phosphatases)
ensure the strict alternation of mitosis and DNA replication
How many genes do CDK catalytic subunits have?
10 genes
How many genes do cyclin regulatory subunits have?
> 20 genes
What do active cyclin-CDK complexes do?
Active Cyclin-CDK complex
Phosphorylates specific substrates
What is the retinoblastoma protein key in?
The retinoblastoma protein is a key substrate of
G1 and G1/S cyclin-dependent kinases
What does unphosphorylated retinoblastoma do?
Unphosphorylated RB binds E2F
preventing its stimulation of S-
phase protein expression
What happens when retinoblastoma is phosphorylated?
Released E2F stimulates expression of more Cyclin E and
S-phase proteins e.g. DNA polymerase, thymidine kinase, PCNA etc.
DNA replication starts
What are the 2 families of cyclin dependent kinase inhibitors?
- CDK inhibitory protein/kinase inhibitory protein (CIP/KIP) family(now called CDKN1)
- Inhibitor of kinase 4 family (INK4)(now called CDKN2))
What is CDKN1 expression stimulated by?
Expression of members of this family stimulated weakly by TGF and strongly by DNA
damage (involving TP53)
What do CDKN1 inhibit?
Inhibit all other CDK-cyclin complexes (late G1, G2 and M)
What are CDKN1 gradually sequestered by?
Are gradually sequestered by G1 CDKs thus allowing activation of later CDKs
What is the expression of CDKN2 stimulated by?
Expression stimulated by TGF-beta
What do CDKN2 specifically inhibit?
Specifically inhibit G1 CDKs (e.g. CDK4 the kinase activated by growth factors)
What induces cyclin expression?
Growth factors induce cyclin expression
What does DNA damage detected at checkpoints trigger?
DNA damage detected at checkpoints
triggers cell cycle arrest or apoptosis
What is the role of TP53 in response to DNA damage?
After kinase activation it leads to:
-DNA repair like excision repair
-If repair not possible then apoptosis
-Expresses CKI to induce cell cycle arrest
What is TP53 destruction by?
TP53 destruction by proteasome
