RVQ2 9. What is the role of Apc in Colon cancer? 10. 11. 2. How can p21, p53, cd
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Question
RVQ29. What is the role of Apc in Colon cancer? 10. 11. 2. How can p21, p53, cdc25, and ATM lead to arrest of the cell cycle? Please explain what these molecules do and how they are affected by each other. 12. What is CAK and what does it do within cell cycle regulation? 13. What is cdc25 and what does it do within cell cycle regulation 14. How does p27 CKI become part of a feedback loop within the cell cycle? 15. Describe the cyclin E & A feed-forward (positive feedback) loop within the regulation of Rb by Cdks 16. Describe how cyclin D interacts with E2F to regulate the cell cycle
RVQ2
9. What is the role of Apc in Colon cancer? 10. 11. 2. How can p21, p53, cdc25, and ATM lead to arrest of the cell cycle? Please explain what these molecules do and how they are affected by each other. 12. What is CAK and what does it do within cell cycle regulation? 13. What is cdc25 and what does it do within cell cycle regulation 14. How does p27 CKI become part of a feedback loop within the cell cycle? 15. Describe the cyclin E & A feed-forward (positive feedback) loop within the regulation of Rb by Cdks 16. Describe how cyclin D interacts with E2F to regulate the cell cycle
9. What is the role of Apc in Colon cancer? 10. 11. 2. How can p21, p53, cdc25, and ATM lead to arrest of the cell cycle? Please explain what these molecules do and how they are affected by each other. 12. What is CAK and what does it do within cell cycle regulation? 13. What is cdc25 and what does it do within cell cycle regulation 14. How does p27 CKI become part of a feedback loop within the cell cycle? 15. Describe the cyclin E & A feed-forward (positive feedback) loop within the regulation of Rb by Cdks 16. Describe how cyclin D interacts with E2F to regulate the cell cycle 9. What is the role of Apc in Colon cancer? 10. 11. 2. How can p21, p53, cdc25, and ATM lead to arrest of the cell cycle? Please explain what these molecules do and how they are affected by each other. 12. What is CAK and what does it do within cell cycle regulation? 13. What is cdc25 and what does it do within cell cycle regulation 14. How does p27 CKI become part of a feedback loop within the cell cycle? 15. Describe the cyclin E & A feed-forward (positive feedback) loop within the regulation of Rb by Cdks 16. Describe how cyclin D interacts with E2F to regulate the cell cycle
Explanation / Answer
9) APC is classified as a tumor suppressor gene. Tumor suppressor genes prevent the uncontrolled growth of cells that may result in cancerous tumors. The protein made by the APC gene plays a critical role in several cellular processes that determine whether a cell may develop into a tumor. The APC protein helps control how often a cell divides, how it attaches to other cells within a tissue, how the cell polarizes and the morphogenesis of the 3D structures or whether a cell moves within or away from a tissue. This protein also helps ensure that the chromosome number in cells produced through cell division is correct. The APC protein accomplishes these tasks mainly through association with other proteins, especially those that are involved in cell attachment and signaling. The activity of one protein in particular, beta-catenin, is controlled by the APC protein. Regulation of beta-catenin prevents genes that stimulate cell division from being turned on too often and prevents cell overgrowth.
Mutations in the adenomatous polyposis coli (APC) gene are not only responsible for familial adenomatous polyposis (FAP) but also play a rate-limiting role in the majority of sporadic colorectal cancers. Colorectal tumours are known to arise through a gradual series of histological changes, the so-called 'adenoma-carcinoma' sequence, each accompanied by a genetic alteration in a specific oncogene or tumour suppressor gene. Loss of APC function triggers this chain of molecular and histological changes. In general, an intestinal cell needs to comply with two essential requirements to develop into a cancer: it must acquire selective advantage to allow for the initial clonal expansion, and genetic instability to allow for multiple hits at other genes responsible for tumour progression and malignant transformation. Inactivation of APC seems to fulfill both requirements. In this short review, I will discuss the role played by APC in providing, when mutated, selective advantage, through constitutional activation of the Wnt signal transduction pathway, and chromosomal instability to the nascent intestinal tumor cell.
11) ATM is a protein that senses break in DNA and then triggers the activation of either of two pathways (depending on whether the cells in G1 or G2). In one pathway, cdc25 becomes, phosphorylated and thus gets inactivated, meaning that if cannot dephosphorylate cdk's. Since the cdk's remain in their phosphorylated and inactive state, they do not move the cell through the next checkpoint. In the other pathyway, ATM causes the stabilization of p53, which then acts as a transcription factor inducing the synthesis of p21, a cdk inhibitor. Inhibitin of cdk's then cause the cell cycle to stall.
12)CDK-activating kinase (CAK) activates the cyclin-CDK complex by phosphorylating threonine residue 160 in the CDK activation loop. CAK itself is a member of the Cdk family and functions as a positive regulator of Cdk1, Cdk2, Cdk4, and Cdk6.
CAK also regulates transcription. Two forms of CAK have been identified; free CAK and TFIIH-associated CAK. Free CAK is more abundant than TFIIH-associated CAK. Free CAK phosphorylates Cdks and is involved in cell cycle regulation.
Cdk activation requires two steps. (1) cyclin must bind to the Cdk. (2) CAK must phosphorylate the cyclin-Cdk complex on the threonine residue 160, which is located in the Cdk activation segment. Since Cdks need to be free of Cdk inhibitor proteins (CKIs) and associated with cyclins in order to be activated, CAK activity is considered to be indirectly regulated by cyclins.
In mammals, activating phosphorylation by CAK can only occur once cyclin is bound. In budding yeast, activating phosphorylation by CAK can take place before cyclin binding. In both humans and yeast, cyclin binding is the rate limiting step in the activation of Cdk. Therefore, phosphorylation of Cdk by CAK is considered a post-translational modification that is necessary for enzyme activity. Although activating phosphorylation by CAK is not exploited for cell-cycle regulation purposes, it is a highly conserved process because CAK also regulates transcription.
13) Cdc25 (cell division cycle 25) is a dual-specificity phosphatase first isolated from the yeast Schizosaccharomyces pombe as a cell cycle defective mutant. Dual-specificity phosphatases are considered a sub-class of protein tyrosine phosphatases. By removing inhibitory phosphate residues from target Cyclin-Dependent Kinases (Cdks), Cdc25 proteins control entry into and progression through various phases of the cell cycle, including mitosis and S (Synthesis) phase.
Cdc25 activates cyclin dependent kinases by removing phosphate from residues in the Cdk active site. Activation of cyclin-dependent kinases in higher eukaryotic cells can be achieved through dephosphorylation by members of the Cdc25 phosphatase family, Cdc25A, Cdc25B and Cdc25C. Cdc25A plays an important role at the G1/S-phase transition. Cdc25B undergoes activation during S-phase and plays a role in activating the mitotic kinase Cdk1/cyclin B in the cytoplasm. Active Cdk1/cyclin B then phosphorylates and activates Cdc25C leading to a positive feedback mechanism and to entry into mitosis. Cdc25A and B are potential human oncogenes. In addition, Cdc25 is a main player of the G2 arrest caused by DNA damage or in the presence of unreplicated DNA.
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