Roles of Smad3 in TGF-beta signaling during carcinogenesis

Abstract

Signaling of transforming growth factor beta (TGF-beta) is mediated through a heteromeric complex of two types of transmembrane receptors and downstream intracellular proteins known as Smads. Alterations of TGF-beta signaling underlie various forms of human cancer and developmental diseases. Human genetic studies have revealed both point mutations and deletions of Smad2 or Smad4 in several types of cancers. However, the role of Smad3 in tumorigenesis is not clear. Recent data indicate that Smad3 also functions as a tumor suppressor by inhibiting cell proliferation and promoting apoptosis. In addition, Smad3 is essential for TGF-beta-mediated immune suppression, and it plays an important role in regulating transcriptional responses that are favorable to metastasis. Therefore, through regulating different transcriptional responses, Smad3 functions as both a negative and positive regulator of carcinogenesis depending on cell type and clinical stage of the tumor.

FIGURE 1

Mechanisms of Smad3 in TGF-β–induced antiproliferative transcriptional responses. In repressing the protooncogene c-Myc, a preexisting cytoplasmic complex containing Smad3, E2F4/5, and p107 likely begins to move into the nucleus in response to ligand stimulation and binds DNA at a RSBE/TIE site in the c-Myc promoter. Smad4 is recruited to this complex as well. In the induction of CDK inhibitors p15^Ink4b and p21^Cip1, a different Smad3/4 complex cooperates with FOXO at a distal promoter element to activate transcription. The PI3K/Akt pathway has the ability to antagonize TGF-β/Smad3 signaling by inhibiting FOXO nuclear localization. The Smad3/4 complex also stimulates transcription in conjunction with Sp1 at a proximal promoter element. Finally, transcription of p15^Ink4b and p21^Cip1 is directly repressed by c-Myc through its association with Miz-1 and/or Smad2/3 at the initiator site. Thus, attenuating c-Myc expression is a prerequisite for induction of p15^Ink4b and p21^Cip1.

FIGURE 2

Mechanisms of Smad3 in TGF-β–mediated proapoptotic transcriptional responses. An activated Smad3/4 complex is required in the nucleus to activate the transcription of GADD45 (along with FOXO) and Bim or DAPK and to repress Bcl-2. p38 MAPK is likely involved in the repression of Bcl-2, but the mechanism is not clear. Three mechanisms have been reported for the PI3K/Akt pathway to dampen the proapoptotic signaling of Smad3: Akt can sequester Smad3 in the cytoplasm by the binding of Smad3, activity of Smad3 can be inhibited by mTOR, or Akt may inhibit FOXO by sequestering it from participating in Smad3-mediated transcription of GADD45.

FIGURE 3

Mechanisms underlying prooncogenic activities of Smad3 during the late stages of carcinogenesis. Smad3 is essential for TGF-β–mediated immune suppression, and it regulates transcriptional responses that are favorable to EMT and metastasis. The induced genes are labeled with upward arrows and repressed ones with downward arrows.