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▲ FIGURE 14-3 Schematic model of Ski-mediated down-regulation of the response to TGFp stimulation. Ski binds to Smad4 in Smad3/Smad4 or Smad2/Smad4 (not shown) signaling complexes and may partially disrupt interactions between the Smad proteins. Ski also recruits a protein termed N-CoR that binds directly to mSin3A, which in turn interacts with histone deacetylase (HDAC), an enzyme that promotes histone deacetylation (Chapter 11). As a result, transcription activation induced by TGFp and mediated by Smad complexes is shut down. [See S. Stroschein et al., 1999, Science 286:771; X. Liu et al., 2001, Cytokine and Growth Factor Rev. 12:1; and J.-W. Wu et al., 2002, Cell 111:357.]

Among the proteins induced after TGFp stimulation are the I-Smads, especially Smad7. Smad7 blocks the ability of activated type I receptors to phosphorylate R-Smad proteins. In this way Smad7, like Ski and SnoN, participates in a negative feedback loop; its induction serves to inhibit intracellular signaling by long-term exposure to the stimulating hormone. In later sections we see how signaling by other cell-surface receptors is also controlled by negative feedback loops.

Loss of TGFp Signaling Contributes to Abnormal Cell Proliferation and Malignancy

Many human tumors contain inactivating mutations in either TGFp receptors or Smad proteins, and thus are resistant to growth inhibition by TGFp (see Figure 23-20). Most human pancreatic cancers, for instance, contain a deletion in the gene encoding Smad4 and thus cannot induce p15 and other cell-cycle inhibitors in response to TGFp. This mutation-defined gene originally was called DPC (deleted in pancreatic cancer). Retinoblas-toma, colon and gastric cancer, hepatoma, and some T- and B-cell malignancies are also unresponsive to TGFp growth inhibition. This loss of responsiveness correlates with loss of type I or type II TGFp receptors; responsiveness to TGFp can be restored by recombinant expression of the "missing" protein. Mutations in Smad2 also commonly occur in several types of human tumors. Not only is TGFp signaling essential for controlling cell proliferation, as these examples show, but it also causes some cells to differentiate along specific pathways, as discussed in Chapter 15. I

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