Smad9 is a new type of transcriptional regulator in bone morphogenetic protein signaling

Abstract

Smad1, Smad5 and Smad9 (also known as Smad8) are activated by phosphorylation by bone morphogenetic protein (BMP)-bound type I receptor kinases. We examined the role of Smad1, Smad5, and Smad9 by creating constitutively active forms (SmadDVD). Transcriptional activity of Smad9DVD was lower than that of Smad1DVD or Smad5DVD, even though all three SmadDVDs associated with Smad4 and bound to the target DNA. The linker region of Smad9 was sufficient to reduce transcriptional activity. Smad9 expression was increased by the activation of BMP signaling, similar to that of inhibitory Smads (I-Smads), and Smad9 reduced BMP activity. In contrast to I-Smads, however, Smad9 did not inhibit the type I receptor kinase and suppressed the constitutively active Smad1DVD. Smad9 formed complexes with Smad1 and bound to DNA but suppressed the transcription of the target gene. Taken together, our findings suggest that Smad9 is a new type of transcriptional regulator in BMP signaling.

Cytoplasmic calcium increase via fusion with inactivated Sendai virus induces apoptosis in human multiple myeloma cells by downregulation of c-Myc oncogene

“…A previous study demonstrated that the cytosolic increase in Ca 2+ induces Smad1 phosphorylation to promote Smad1 nuclear translocation [40]. In addition, either SMAD1 or SMAD1/5/8 regulates c-Myc transcription by binding to SMAD4 to form a Smad complex [41–43]. As shown in Figure 7A, the transient knockdown of Smad4 in NCI-H929 cells by siRNA inhibited the HVJ-E-induced suppression of c-Myc transcription.…”

Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma

“…GDF6 has been shown to act through BMPR1A (ALK3) (35), and we found that treatment with DMH1 reduced p-SMAD1/5/8 levels and decreased cell growth and tumorigenicity ( Figure 3F and Supplemental Figure 7, D and E). To test the relationship of GDF6 to SMAD1 in genetic epistasis analyses, we expressed a phosphomimetic variant of SMAD1, SMAD1DVD, in A375 cells (Supplemental Figure 7F) (39). Whereas GDF6 knockdown abrogated cell growth and the tumorigenic potential of A375 control cells, A375-SMAD-1DVD cells subjected to GDF6 knockdown were rescued, showing robust growth in colony formation and xenotranplantation assays ( Figure 3G and Supplemental Figure 7, G and H).…”

A comprehensive transcriptomic view on the role of SMAD4 gene by RNAi-mediated knockdown in porcine follicular granulosa cells

“…5 and Supplementary Table S4). In general, SMAD6 and SMAD7 play negative feedback loop in the TGF-β/SMAD signaling pathway and are considered as potential regulators of ovarian function (Nakao et al 1997, Uchida et al 2000, Tsukamoto et al 2014, Li 2015, while SMAD9 suppresses intracellular bone morphogenetic protein (BMP) signaling (Tsukamoto et al 2014). By decreasing the levels of these inhibitory SMADs, SMAD4-silencing might reduce inhibitory SMAD-related pathways or ovarian function in porcine follicular GCs.…”