In 1971, Dr. Judah Folkman published the \"angiogenic hypothesis\" suggesting th
ID: 78083 • Letter: I
Question
In 1971, Dr. Judah Folkman published the "angiogenic hypothesis" suggesting that a tumor cannot grow beyond 1-2 millimeters without the development of new blood vessels (angiogenesis) that provide access to oxygen and nutrients. During the 1990s, it was discovered that vascular endothelial growth factor (VEGF) stimulates migration and proliferation of the cells that form blood vessels, leading to the formation of new blood vessels. VEGF binds to receptor tyrosine kinases (RTKs) on the cell surface and causes the RTKs to dimerize and become active, thereby initiating an intracellular signaling cascade that stimulates cell division and inhibits apoptosis. Many cancer cells secrete high levels of VEGF and increased VEGF expression in a tumor is correlated with a poor medical outcome for the patient. You work for a biotechnology company that seeks to create anticancer drugs that prevent growth of tumors and or cause tumors to shrink, while leaving normal cells relatively untouched. Your company has purchased the rights to therapeutic uses of VEGF derived proteins as anti-tumor drugs. You have found that the VEGF protein has 2 domains, one involved in receptor binding, the other is required for dimerization of VEGF. You propose to make mutant versions of the protein that will act as antagonists of the receptor to be given to patients as an IV treatment as a way to inhibit the endogenous VEGF secreted by the tumor. a. Which of the 2 domains should you mutate (receptor binding or dimerization)? b. How do you expect the introduction of the mutant protein into the bloodstream of patients to block tumor progression (in other words, why did you change the domain in part a)? Multicellular organisms can selectively remove unnecessary cells using a cellular suicide process. What is this process called? Briefly describe or use a figure to show how the pathway is activated when a survival signal is no longer supplied to a cell.Explanation / Answer
a). We would mutate the domain involved in the dimerization of receptor tyrosine kinase (RTKs). Native receptor domain (with mutated dimerization domain) would compete with the receptor binding.
b). The protein bound to the receptor domain would not lead to the tumor growth since the dimerization of RTK would not take place due to the induced mutation.
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