Cell signaling and Apoptosis. Valproic acid is a drug that has been used to trea

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Cell signaling and Apoptosis. Valproic acid is a drug that has been used to treat bipolar disorder and epilepsy. More recently, researchers have found that human breast cancer cell lines are sensitive to treatment with Valproic acid. Breast cancer cell lines that are overexpressing HER2 (Human EGFR 2) are more sensitive than other cell lines.   Interestingly, Valproic acid affects the cell in a number of ways including alteration in the levels of p21, caspase 3 activity, acetylation of heat shock proteins (chaperones) and acetylation of a-tubulin. Let’s investigate the effects of VPA!

a. In the Graph A, the researchers assayed for the effects of VPA in breast cancer cell lines overexpressing HER2. They measured cell viability (whether the cells were alive). In general, what was the effect of VPA on the cells over time? Rubric (2): One sentence describes effects of increasing concentrations of VPA with regard to the dependent variable (cell viability)

b. Graph B below shows the effect of VPA treatment (x-axis) on the expression of p21 (amount of protein present in the cell). Explain the result in graph B and interpret why this result would decrease cell division in these cancer cells (be specific!). Rubric (6): one sentence states the effect of VPA on levels of p21 protein in the cell (2). Correct explanation includes function of p21 protein (2) and specific reasons why the observed levels of p21 effects would decrease cell division (2).

c. VPA treatment also increased the expression of the cleaved form of Caspase-3 (active). Describe how active caspase is formed from procaspase-3. Rubric (2): look in your notes or book, how do you form an active caspase?

d. In general, the graph C shows an increased amount of cleaved caspase-3 after VPA treatment (x-axis shows hours of VPA treatment). Explain this result with regard to the results in Graph A. Rubric (4): Statement explains the result in graph A using the information in the graph C.

Styles ecently, researchers have found that human breast cancer lproic acid. Breast cancer cell lines that are e more sensitive than other cell lines. Interestingly, f ways including alteration in ne levels of p21, caspase 3 A 120 SKBR3 100 ?60 40.-24 h 120 h 0 0.5 1 2 3 5 10 VPA (mM) A treatment (x-axis) on the expression of esult in graph B and interpret why this result would decrease cificl). Rubric 6): one sentence states the effect of VPA on levels of pzt protein t protein 12) and specitic ressons why the observed levels of p21 effects would p21 (amount of pression of the cleaved form of caspase 3 (active), Describe

Explanation / Answer

a) As the concentations of VPA is increased , the cell viability goes on decreasing .

b) As the Valproic acid cncentration is increased from zero to one , we observe a slight lowering of the gene expression of p21 gene . After that, the concentration increase will cause increase in the gene expression of the p21 gene.

This is because the VPA sensitizes the cytotoxic effects of etoposides by increasing the cell differentiation and u regulating the gene expression of p21 and topoisomerase -II.

c) Caspase -3 which resides in the zymogen inactive , is activated by the apoptotic cell processes . This type of activation is a catalytic activation which may be extrinsic or intrinsic .

The activated caspase-3 are inactivated by the inhibitor of apoptosis type of family of proteins.

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