Personal ID: C3735427
Name: Erika Azzopardi
Assignment number: Tutor marked assignment 03 (TMA03) - Cancer
Module: S807 - Molecules in medicine
Question 1a Figure 1: Summary of the cell cycle illustrating: G1; S; G2 and M phases. Cells grow and prepare to synthesize DNA in the G1 phase. Cells move towards end of G1 phase to pass through G1-checkpoint. G1-checkpoint determines if a cell is suitable for cell division by checking for damaged DNA. On check completion, cells owning undamaged DNA move to the S phase. Cells with damaged DNA are arrested and "commit suicide" via apoptosis.
Proto-oncogenes are normal genes which produce signals to guide a cell to divide or ‘commit suicide’. These genes are inspected by checkpoints. When proto-oncogenes…show more content… Alkylating drugs such as cisplatin can perform cross-linking in the same DNA strand.
Figure available from: Hurley, L.H. (2002) ‘DNA and its Associated Processes as Targets for Cancer Therapy.’ Nature Reviews Cancer, 2 (3), pp. 188-200.
Anthracycline antibiotics are also considered as cytotoxic. They harm DNA by introducing a drug molecule between the bases of the DNA strands or block topoisomerase enzymes and radical generation. Topoisomerases catalyse DNA supercoiling (Hurley, 2002). Blocking these enzymes will disrupt DNA. Doxorubicin (Figure 3) is a non-specific DNA-intercalating drug. It is very effective since it is more selective towards cancer cells than normal cells as it blocks the DNA covalently-bound topoisomerase II enzyme (Hurley, 2002). Figure 3: Molecular structure of Doxorubicin (Drawn by using Symyx Draw).
This was a significant finding since it showed that DNA activities (transcription, replication and repair) can be also used as drug targets. Targeting DNA activities offers a great advantage since it can be easier for cancer drugs to distinguish between the DNA activities that happen in cancer and normal cells. DNA activities need proteins to bind to the DNA molecule. Inhibiting the proteins which participate in DNA activities of cancer cells will promote drug selectivity. Recent drugs target particular deregulated signal pathways due to the participation…show more content… & Csermely, P. (2005) ‘Molecular chaperones as regulatory elements of cellular networks.’ Current Opinion in Cell Biology, 17, 210-215.
Question 3b (352 words – w/o in-text citations)
Stressful conditions (e.g. high temperatures) alter the normal cellular environment. To regain homeostasis, cells generate ‘heat shock proteins’ (Hsp’s) to act as molecular chaperones (Porter et al., 2010). One particular Hsp is the highly conserved ATP-dependent Hsp90 (90kDa molecular weight) (Buchner and Li, 2013).
Hsp90 functions in various cellular pathways in cell proliferation and cellular stress-survival response. Hsp90 molecular chaperone guides diverse client proteins to keep the correct folding conformation, function and stability (Porter et al., 2010). Most of its client proteins are protein kinases and transcription factors which participate in signal transduction pathways.
Two major Hsp90 isoforms exist: Hsp90-alpha and Hsp90-beta (Hartl et al., 2011). Both isoforms have very similar structures and can be overexpressed in malignant cells.
Hsp90 has three functional regions: N-terminal ATP-binding; middle protein-binding (M); and C-terminal dimerisation domains. Hsp90 forms an ‘open’ or a ‘closed’ conformation. ATP-binding activates an array of conformational changes until Hsp90 achieves a more compact (closed)
