Cell Cycle, Apoptosis, and Cancer Flashcards
Restriction Point (R)
a. two hours prior to S phase (in G1)
b. if growth factors are LIMITED
G1 checkpoint
a. timing similar to restriction point (in G1)
b. occurs in response to DNA damage
G2 checkpoint
a. verify complete genomic duplication (is in G2 phase)
Metaphase Checkpoint
a. ensures chromosomes attached to mitotic spindle
b. beginning of M phase
Proteolysis of cyclins
A. APC/C activated by binding to Cdc20
B. activated APC/C poly-ubiquitinates its substrates
C. APC/C substrate proteins include S- and M-cyclin proteins
D. Leads to addition of polyubiquitin to S- and M-cyclin complexes
E. cyclins targeted for destruction by proteasome
F. absence of cyclins inactivates Cdks
G. Cdks dephosphorylated (inactive) after cyclins are degraded
Replicative Cell senescence
- human skin fibroblasts in cell culture stop dividing after 30-50 population doublings, even when abundant GFs are present in culture medium
- this type of gaining of somatic cell cultures is termed replicative cell senescence and appears to be due to a progressive shortening of the telomeres of chromosomes with each cell division
- many somatic cells lack the enzyme telomerase which is necessary to maintain the telomeres by preserving their length as well as protecting them from damage by promoting end cap structures
- dna damage leads to p53-mediated cell cycle arrest at G1 checkpoint; thought that agin-induced DNA damage could be mediated by an accumulation of reactive oxygen species
p53 and p21–> cell cycle arrest
- p53 (“guardian of the genome”) is a TF
- normally degraded by proteasome in quiescent cells ; E3 ubiquitin ligase (MDM2) keeps 53 inactive through degradation
- DNA damage= increased protein kinase activity
- p53 protein stabilized/ activated by phosphorylation
- activation of p53 leads to increased transcription of specific CKI (p21)
- binding and inactivation of cyclin-CDK complexes by p21 causes cell cycle arrest
Apaf1 and Intrinsic pathway
- activated BAX self-aggregates
- located on mitochondrial outer membrane
- induces release of cytochrome c
- Ca2+ released from SR
- apoptosis formed by binding to Apaf1
- cytochrome C/Apaf1 complex activates caspace 9
- caspace cascade leading to apoptosis
Proto-oncogene
- expression leads to growth factors, receptors for GFs and hormones, TFs, signal transducers
- GOF mutation makes it an oncogene
a. point mutation, deletion, gene amplification, chromosomal translocation - Oncogene expression:
a. leads to increased expression of protein products, expression of altered protein (oncoprotein) that doesn’t respond to normal signals
Tumor Suppressor Functions
- represses cell cycle progression
- promotes apoptosis (damaged cell death)
- couples DNA damage to cell cycle
- DNA repair proteins
A. ex. BRCA (breast cancer gene–> if both lost= increased chance for breast cancer); decreased DNA repair leading to increased inactivation of tumor suppressors –> activation of oncogenes
Tumor Suppressor Examples
- RB1 Gene encodes pRb (Rb) protein–> 100% of retinoblastoma
- TP53 encodes p53 (65% of colon; 30-50% breast; 50% lung)
- PTEN–> phosphates and tennis homolog (70% of prostate cancers)
- APC–> Adenomatous polyposis coli (colon cancer)
Hallmarks of Cancer
- Self-sufficiency in growth signals (ability to grow alone)
- Evading growth suppressors (tumor suppressor failure)
- Activating invasion and metastasis
- Enabling replicative immortality (continuous expression of telomerase)
- inedible angiogenesis (allow abc to go to area and feed cancer cells)
- resisting cell death (from apoptosis)
Viral Oncogenesis
a. non transforming virus infects host
b. viral genome integrates into host genome, adjacent to photo-oncogene
c. virus replicates; some may contain hosts proto-oncogene
d. photo-oncogene mutates into an oncogenes
e. virus containing oncogene infects normal cell, transforming it into a tumor cell
Sites of action of chemotherapeutic agents
a. Alkylating agents–> all phases of cycle
- block DNA replication
b. Topoisomerase 1 inhibitors –> at S phase
- topotecan
c. Antimetabolites–> S phase
- inhibits enzymes involved in DNA synthesis
d. Cytotoxic antibiotics–> S phase and G2 phase
- intercalates between bases in DNA to inhibit DNA synthesis
e. Topoisomerase 2 inhibitors–> S, G2, and M
- etoposide, teniposide
f. Mitotic inhibitors–> Mitosis phase
- arrests cel lin mitosis during metaphase
Trastuzumab/ Herceptin
inhibits HER2 overexpression
- blocks cleavage dimerization, and can cause Her2 to be degraded + tumor-cell lysis
- Breast Cancer chemotherapy
