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Question 6#

Dysregulation of transforming growth factor-beta (TGF-β) signaling is associated with all of the following EXCEPT:

A) Cancer
B) Inguinal hernias
C) Marfan syndrome
D) Thoracic aortic aneurysm

Correct Answer is B


Resistance to transforming growth factor-beta's (TGF-β) anticancer action is one hallmark of human cancer cells. TGF-β receptors and SMADs are identified as tumor suppressors. The TGF-β signaling circuit can be disrupted in a variety of ways and in different types of human tumors. Some lose TGF-β responsiveness through downregulation or mutations of their TGF-β receptors. The cytoplasmic SMAD4 protein, which transduces signals from ligand-activated TGF-β receptors to downstream targets, may be eliminated through mutation of its encoding gene. The locus encoding cell cycle inhibitor p 15INK4B may be deleted. Alternatively, the immediate downstream target of its actions, CDK4, may become unresponsive to the inhibitory actions of p15INK4B because of mutations that block p15INK4B binding. The resulting cyclin D/CDK4 complexes constitutively inactivate tumor suppressor pRb by hyperphosphorylation. Finally, functional pRb, the end target of this pathway, may be lost through mutation of its gene. For example, in pancreatic and colorectal cancers, 100% of cells derived from these cancers carry genetic defects in the TGF-β signaling pathway. Therefore, the antiproliferative pathway converging onto pRb and the cell division cycle is, in one way or another, disrupted in a majority of human cancer cells. Besides cancer, dysregulation ofTGF-β signaling also has been associated with other human diseases such as Marfan syndrome and thoracic aortic aneurysm.