Figure 18–13 How the chemical ABT737 inhibits anti-apoptotic Bcl2 family proteins. As shown in Figure 18–10B, an apoptotic signal results in activation of Bh3-only proteins, which interact with a long hydrophobic groove in anti-apoptotic Bcl2 family proteins, thereby preventing them from blocking apoptosis. Using the crystal structure of the groove, the drug shown in (A), called ABt-737, was designed and synthesized to bind tightly in the groove, as shown for the anti-apoptotic Bcl2 family protein, BclXL, in (B). By inhibiting the activity of these proteins, the drug promotes apoptosis in any cell that depends on them for survival. (pDB code: 2YXJ.) how many forms of programmed cell death exist? What are the underlying mechanisms and benefits of each?
thousands of caspase substrates have been identified. Which ones are the critical proteins that must be cleaved to trigger the major cell remodeling events underlying apoptosis?
how did the intrinsic pathway of apoptosis evolve, and what is the advantage of having mitochondria play such a central role in regulating apoptosis?
how are “don’t eat me” signals eliminated or inactivated during apoptosis to allow the cells to be phagocytosed?
Which statements are true? Explain why or why not.
18–1 In normal adult tissues, cell death usually balances cell division.
18–2 Mammalian cells that do not have cytochrome c should be resistant to apoptosis induced by DNA damage.
Discuss the following problems.
18–3 One important role of Fas and Fas ligand is to mediate the elimination of tumor cells by killer lymphocytes. In a study of 35 primary lung and colon tumors, half the tumors were found to have amplified and overexpressed a gene for a secreted protein that binds to Fas ligand. How do you suppose that overexpression of this protein might contribute to the survival of these tumor cells? Explain your reasoning.
18–4 Development of the nematode Caenorhabditis elegans generates exactly 959 somatic cells; it also produces an additional 131 cells that are later eliminated by apoptosis. Classical genetic experiments in C. elegans isolated mutants that led to the identification of the first genes involved in apoptosis. Of the many mutations affecting apoptosis in the nematode, none have ever been found in the gene for cytochrome c. Why do you suppose that such a central effector molecule in apoptosis was not found in the many genetic screens for “death” genes that have been carried out in C. elegans?
18–5 Imagine that you could microinject cytochrome c into the cytosol of wild-type mammalian cells and of cells that were doubly defective for Bax and Bak. Would you expect one, both, or neither type of cell to undergo apoptosis? Explain your reasoning.
18–6 In contrast to their similar brain abnormalities, newborn mice deficient in Apaf1 or caspase-9 have distinctive abnormalities in their paws. Apaf1-deficient mice fail to eliminate the webs between their developing digits, whereas caspase-9-deficient mice have normally formed digits (Figure Q18–1). If Apaf1 and caspase-9 function in the same apoptotic pathway, how is it possible for these deficient mice to differ in web-cell apoptosis?