#1 Cowden Syndrome (CS) is an inherited condition in which patients develop canc
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Question
#1 Cowden Syndrome (CS) is an inherited condition in which patients develop cancers at very high rates and in many different tissues and organs. Patients with CS can even present with independent non-metastatic tumors in multiple organs at the same time. CS is a rare example of an autosomal dominant disease condition. (Rare because of the strong negative selection of such a lethal disease.) In most cases, patients with CS harbor mutations in the tumor suppressor gene PTEN. PTEN is one of the most important tumor suppressors in the human body, behind only p53 and pRb, and mutated in about 10% of human cancers. However, mutations in tumor suppressor genes generally induce a loss-of-function, making the dominant nature of CS even stranger.
1.) What is the normal function of PTEN? (Hints to answer this: PTEN is a phosphatase – what is its target? What enzyme that we’ve already learned about is it antagonistic toward? What is the result of this antagonism?)
2.) There are a variety of PTEN mutations that can cause CS, but some of them actually target a specific sequence in the protein: -K-K-K-R-K-. What does this sequence likely do, and what is the possible effect of the mutation?
3.) How would a mutation in the –K-K-K-R-K- region of PTEN lead to the condition known as Cowden Syndrome?
Explanation / Answer
1. PTEN usually dephosphorylates the phosphatidylinositol (3,4,5)-trisphosphate or PIP3 specifically at the 3` phosphate of the inositol ring it results in the formation of PIP2,which is animportant event in the inhibition of AKT signaling pathway. In addition, PTEN's phosphatase activity plays an important role in the regulation of cell cycle by preventing a rapid multiplication and growth of the cell, hence, it is called as tumor suppressor protein. I think, you have learned about the enzyme phosphatidylinositol 3-kinase is an antagonist of PTEN. Increased PI3K activity leads to persistent signaling (Akt) to the cell resulting increased their survival, growth, proliferation, and migration activity, angiogenesis and cancer. The PI3K-Akt signaling usually regulates the transcription and function of PTEN by upregulating the NF-B, which is an agonist of PPAR/ receptor and TNF involve in the repression of PTEN expression.
2. It seems that it is a nuclear localization sequence, a mutation in this region leads to PTEN does not enter or inefficient localization into the nucleus. So that it can be accumulated in the cytoplasm. Nuclear localization is a stimulus for apoptosis if a mutation occurs in that basic amino acids rich sequence, no apoptosis will occur that leads to cancer.
3. PTEN protein does not function properly that leads to hyperactivity of the mTOR pathway. Typically PTEN's phosphatase activity negatively regulates mTOR signaling via interfering with the action of PI3K, which is an upstream effector of mTOR. mTOR is a serine/threonine protein kinase, typically regulates the cell growth, proliferation, motility, survival, protein synthesis, autophagy, and transcription. It also belongs to the 3K protein family.
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