Mastermind-like 1 (MAML1) is a transcriptional co-activator in the Notch signaling pathway. Recently, however, several reports revealed novel and unique roles for MAML1 that are independent of the Notch signaling pathway. We found that MAML1 enhances the transcriptional activity of runt-related transcription factor 2 (Runx2), a transcription factor essential for osteoblastic differentiation and chondrocyte proliferation and maturation. MAML1 significantly enhanced the Runx2-mediated transcription of the p6OSE2-Luc reporter, in which luciferase expression was controlled by six copies of the osteoblast specific element 2 (OSE2) from the Runx2-regulated osteocalcin gene promoter. Interestingly, a deletion mutant of MAML1 lacking the N-terminal Notch-binding domain also enhanced Runx2-mediated transcription. Moreover, inhibition of Notch signaling did not affect the action of MAML1 on Runx2, suggesting that the activation of Runx2 by MAML1 may be caused in a Notch-independent manner. Overexpression of MAML1 transiently enhanced the Runx2-mediated expression of alkaline phosphatase, an early marker of osteoblast differentiation, in the murine pluripotent mesenchymal cell line C3H10T1/2. MAML1−/− embryos at embryonic day 16.5 (E16.5) had shorter bone lengths than wild-type embryos. The area of primary spongiosa of the femoral diaphysis was narrowed. At E14.5, extended zone of collagen type II alpha 1 (Col2a1) and Sox9 expression, markers of chondrocyte differentiation, and decreased zone of collagen type X alpha 1 (Col10a1) expression, a marker of hypertrophic chondrocyte, were observed. These observations suggest that chondrocyte maturation was impaired in MAML1−/− mice. MAML1 enhances the transcriptional activity of Runx2 and plays a role in bone development.
Vyšlo v časopise: MAML1 Enhances the Transcriptional Activity of Runx2 and Plays a Role in Bone Development. PLoS Genet 9(1): e32767. doi:10.1371/journal.pgen.1003132 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003132
1. KomoriT (2002) Runx2, a multifunctional transcription factor in skeletal development. J Cell Biochem 87 : 1–8.
2. DucyP, ZhangR, GeoffroyV, RidallAL, KarsentyG (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89 : 747–754.
3. HongJH, HwangES, McManusMT, AmsterdamA, TianY, et al. (2005) TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309 : 1074–1078.
4. WangW, WangYG, ReginatoAM, GlotzerDJ, FukaiN, et al. (2004) Groucho homologue Grg5 interacts with the transcription factor Runx2-Cbfa1 and modulates its activity during postnatal growth in mice. Dev Biol 270 : 364–381.
5. BermanSD, YuanTL, MillerES, LeeEY, CaronA, et al. (2008) The retinoblastoma protein tumor suppressor is important for appropriate osteoblast differentiation and bone development. Mol Cancer Res 6 : 1440–1451.
6. VegaRB, MatsudaK, OhJ, BarbosaAC, YangX, et al. (2004) Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 119 : 555–566.
7. OyamaT, HarigayaK, MuradilA, HozumiK, HabuS, et al. (2007) Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo. Proc Natl Acad Sci USA 104 : 9764–9769.
8. FortiniME (2002) Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling. Nat Rev Mol Cell Biol 3 : 673–684.
9. LubmanOY, KorolevSV, KopanR (2004) Anchoring notch genetics and biochemistry; structural analysis of the ankyrin domain sheds light on existing data. Mol Cell 13 : 619–626.
10. NamY, SlizP, SongL, AsterJC, BlacklowSC (2006) Structural basis for cooperativity in recruitment of MAML co-activators to Notch transcription complexes. Cell 124 : 973–983.
11. ZhaoY, KatzmanRB, DelmolinoLM, BhatI, ZhangY, et al. (2007) The notch regulator MAML1 interacts with p53 and functions as a co-activator. J Biol Chem 282 : 11969–11981.
12. Alves-GuerraMC, RonchiniC, CapobiancoAJ (2007) Mastermind-like 1 Is a specific co-activator of β-catenin transcription activation and is essential for colon carcinoma cell survival. Cancer Res 67 : 8690–8698.
13. ShenH, McElhinnyAS, CaoY, GaoP, LiuJ, et al. (2006) The Notch co-activator, MAML1, functions as a novel co-activator for MEF2C-mediated transcription and is required for normal myogenesis. Genes Dev 20 : 675–688.
14. JinB, ShenH, LinS, LiJL, ChenZ, et al. (2010) The mastermind-like 1 (MAML1) co-activator regulates constitutive NF-kappaB signaling and cell survival. J Biol Chem 285 (19)
14356–65.
15. HiltonMJ, TuX, WuX, BaiS, ZhaoH, et al. (2008) Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med 14 : 306–314.
16. EnginF, YaoZ, YangT, ZhouG, BertinT, et al. (2008) Dimorphic effects of Notch signaling in bone homeostasis. Nat Med 14 : 299–305.
17. NakanishiK, ChanYS, ItoK (2007) Notch signaling is required for the chondrogenic specification of mouse mesencephalic neural crest cells. Mech Dev 124 : 190–203.
18. ArnoldMA, KimY, CzubrytMP, PhanD, McAnallyJ, et al. (2007) MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev Cell 12 (3)
377–89.
19. GeoffroyV, DucyP, KarsentyG (1995) A PEBP2 alpha/AML-1-related factor increases osteocalcin promoter activity through its binding to an osteoblast-specific cis-acting element. J Biol Chem 270 (52)
30973–9.
20. KitagawaM, OyamaT, KawashimaT, YedvobnickB, KumarA, et al. (2001) A human protein with sequence similarity to Drosophila mastermind coordinates the nuclear form of notch and a CSL protein to build a transcriptional activator complex on target promoters. Mol Cell Biol 21 (13)
4337–46.
21. LinSE, OyamaT, NagaseT, HarigayaK, KitagawaM (2002) Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling. J Biol Chem 277 (52)
50612–20.
22. JarriaultS, BrouC, LogeatF, SchroeterEH, KopanR, et al. (1995) Signalling downstream of activated mammalian Notch. Nature 377 (6547)
355–8.
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