A 54-year-old woman is evaluated for progressive constipation, anorexia, and a 5.4-kg (12-lb) weight loss over the past several months. Physical examination is unremarkable. Stool guaiac test is positive, and a colonoscopy is performed. An exophytic mass is identified in the sigmoid colon. The patient undergoes a left hemicolectomy, and histopathology of the surgical specimen is positive for adenocarcinoma. Molecular testing of the cancer cells reveals a mutation in the KRAS gene that results in constitutive activation of the Ras protein. Under normal circumstances, this protein is only active when bound to which of the following substances?

Question

A 54-year-old woman is evaluated for progressive constipation, anorexia, and a 5.4-kg (12-lb) weight loss over the past several months.  Physical examination is unremarkable.  Stool guaiac test is positive, and a colonoscopy is performed.  An exophytic mass is identified in the sigmoid colon.  The patient undergoes a left hemicolectomy, and histopathology of the surgical specimen is positive for adenocarcinoma.  Molecular testing of the cancer cells reveals a mutation in the KRAS gene that results in constitutive activation of the Ras protein.  Under normal circumstances, this protein is only active when bound to which of the following substances?

Quizplus · Accepted Answer

11ec160b_3698_af75_9249_db49b8e2523a_MD0001_00 RAS genes code for a family of small G-proteins involved in signal transduction in the Ras-MAPK pathway. Ras proteins exist in 2 different states: an inactive GDP-bound state and an active GTP-bound state. Ras becomes activated when a growth factor ligand binds to a receptor tyrosine kinase located on the cell membrane, causing autophosphorylation of the receptor. This triggers binding of adaptor proteins that interact with Ras, promoting GDP removal and GTP binding. Activated Ras then begins a phosphorylation cascade that results in the activation of mitogen-activated protein kinase (MAPK), which enters the nucleus to influence gene transcription. Ras proteins have intrinsic GTPase activity that allows them to hydrolyze GTP; this mechanism prevents accumulation of active Ras (GTP-bound) in the absence of hormonal signaling. RAS gene mutations can lead to decreased intrinsic GTPase activity; this results in a constitutively activated Ras protein that causes constant and unregulated cell proliferation. RAS mutations are commonly identified in cancerous tumors, specifically colorectal and pancreatic malignancies. (Choices A and C) ATP serves as a phosphate source for kinase-dependent phosphorylation reactions involved in numerous intracellular signaling pathways. It is also used as a substrate to produce cyclic AMP (cAMP) in the cAMP second messenger system. (Choice B) Ca²⁺ is important for cell signaling as its intracellular presence alters the function of many proteins and enzymes. Ca²⁺ is required for many basic physiologic activities including apoptosis, muscular contraction, and neuronal transmission. (Choice E) IP₃ is the water-soluble component of the IP₃/DAG second messenger system. IP₃ acts on the endoplasmic reticulum to cause intracellular Ca²⁺ release while DAG remains in the cell membrane and activates membrane-bound protein kinases. Educational objective: Regulation of the Ras-MAPK signal transduction pathway requires a balance between active (GTP-bound) and inactive (GDP-bound) Ras proteins. RAS gene mutations, which result in constitutively activated Ras proteins, are implicated in the development of malignant tumors. __________ References: MEK inhibitors: a therapeutic approach to targeting the Ras-MAP kinase pathway in tumors. (http://www.ncbi.nlm.nih.gov/pubmed/15180527)

A 54-Year-Old Woman Is Evaluated for Progressive Constipation, Anorexia, and a 5.4-Kg