Normal cell cycle
In order to understand the progression from normal cell to cancer we have to understand the molecular basis for the dividing cell which must pass through G0 to G1 (growth) phases and from then on to S phase (see chapter 15). Cyclins and cyclin dependent kinases help to drive this progression. Cyclins are synthesized to activate cyclin dependent kinases (CDK) and then decline in concentration. There are about 15 cyclins which have been identified. Amongst the best known are the following- cyclin D, E, A and B. They bind to one or more of the CDKs. Cyclin D binds to CDK4 during the G1 phase and forms a cyclin D-CDK4 complex. This complex phosphorylates the retinoblastoma susceptibility protein called RB for short. When RB is phosphorylated it increases cell replication by dissociating the complex which RB forms with transcription factor E2F in a state of hypophosphorylation. This has the function of inhibiting E2F transcription activities. Cylin E now forms complex with CDK2 which takes the cell through the processes of G1 and S phases which leads to stupendous DNA synthesis as seen in the synthesis (S) phase causing progression to prophase of mitosis. Cyclin B-CDK1 complex then propels the state beyond prophase and this is activated by protein phosphatase (Cdc 25). It is the complex cyclinB-CDK1 activation that leads to breakdown of the nuclear envelope causing the initiation of mitosis. When cyclin B-CDK1 complex is activated it then causes exit from cell division. The absence of cyclin E in its two isoforms (E1 and E2) prevent cells in resting phase from entering the cell cycle.
CDK inhibitors inhibit the activation of cyclin-CDK complexes and there are of two main classes
· Cip/Kip inhibitors with three component of p21, p27 and p 57
· INK4/ARF family of inhibitors
These are tumor suppressors. There are also two check points which provide internal control of cell cycle.
· G1/S transition checkpoint
· G2/M transition checkpoint
Signal transducing proteins
Normal signaling proteins have been mentioned in chapter 9. They assist all cells in signal transduction but there are oncoproteins which mimic the functions of these signaling proteins and they are located in the inner aspect of the cell membranes of cells and function in tumor induction. The best known oncoprotein is the RAS family of G proteins (guanine triphosphate (GTP)) binding proteins. They form the RAS oncogene. Others are
· Dysregulation of cyclins and cyclin dependent kinases
· MYC oncogene
· Transcription factors
Genes which function as tumor suppressor
· TGF-B pathways
· NF-1 gene
· NF-2 gene
· VHL (von Hippel Lindau) gene
· PTEN (phosphatase and tensin homologue deleted on hormone 10) gene
· WT-1 gene
· Patched (PTCH) gene
· KLF6 gene
· The INK4a/ARF locus
Table: Tyrosine Kinases Are activated by Multiple Genetic Events in human Cancersa After Morin, Trent, Collins and Vogelstein (2005)
1. Translocations generate fusion proteins with BCR, TEL, or NPM. Oligomerization leads to activation of the kinase by cross-phosphorylation.
2. Overexpression causing receptor dimerization in absence of ligand.
3. Gain-of-function point mutation leading to receptor dimerization and kinase activation.
4. Autocrine growth pathway
5. Overexpression of ligands such as VEGF or angiopoietins by stroma or tumor cells
ABL, ALK, FGFR, JAK2, PDGFR, TRKC
EGFR family, IGFR PDGFR, FGFR family, c-MET
Acute and chronic leukemias, fibrosarcoma
Breast, ovarian, lung, gastric, prostate, glioblastoma, others
Gastrointestinal stromal tumors
Medullary thyroid CA
a Deregulation of protein tyrosine kinase is a common genetic event leading to the development of human neoplasia. Tumor cells are highly mutagenic and have defects in DNA-damage checkpoints. This permits the outgrowth of tumor clones with multiple genetic anomalies, some of which promote tumor progression by increasing proliferation, enhancing resistance to apoptosis, and promoting angiogenesis.
Abbrevations: BCR, breakpoint cluster region; TEL, Ets-family transcription factor. NPM, nucleophosmin; ABL, Abelson tyrosine kinase; ALK, anaplastic lymphoma kinase; FGFR, fibroblast growth factor receptor; JAK2, Janus kinase 2; PDGFR, platelet-derived growth factor receptor; TRKC, neurotropin tyrosine receptor kinase C; EGFR, epidermal growth factor receptor, IGFR, insulin-like growth factor receptor; c-MET, receptor for hepatocyte growth factor (HGF); c-KIT, receptor for stem cell factor; c-RET, receptor for glial-derived neutrophic factors; VEGFR, vascular endothelial growth factor receptor; TIE2, angiopoietin receptor.
|Transport of protons across the inner and outer lamellae of inner mitochondrial membrane by the electron transport system (flavoprotein-cytochrome system), with return movement of protons down the protein gradient generating ATP.|
Electronic School of Medicine
Creator: Oluwole Ogunranti