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Gene Review:

Defb4 - defensin beta 4

Mus musculus

Synonyms: 2310001F05Rik, BD-4, Bdef4, Beta-defensin 4, Defensin, beta 4, ...

Sansom, O.J. et al., Schofield, D.A. et al., Millar, C.B. et al., Rivas-Santiago, B. et al., Schofield, D.A. et al., et al.

Schofield, Westwater, Balish, Schofield, Westwater, Balish,

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Disease relevance of Defb4

Induction of mBD4 expression in response to gastric candidiasis, however, was dependent on the immune competency of the host [1].
The kinetics of gene expression and the cellular source of murine beta -defensin-3 (mBD3) and murine beta -defensin-4 (mBD4) were determined in mouse models of progressive pulmonary tuberculosis and latent infection induced by high or low infecting doses, respectively [2].

High impact information on Defb4

The base excision repair (BER) enzyme MED1 (also known as MBD4) interacts with the MMR protein MLH1 [3].
The MBD4 active site is situated in a cleft that likely orients and binds DNA [4].
MBD-4 mRNA was expressed in the esophagus, tongue, and trachea but not in any of 20 other tissues surveyed [5].
As MLH1 and other MMR proteins have been functionally linked to apoptosis, we asked whether MBD4 also plays a role in mediating the apoptotic response within the murine small intestine [6].
MBD4 deficiency reduces the apoptotic response to DNA-damaging agents in the murine small intestine [6].

Biological context of Defb4

Our results establish a novel functional role for MBD4 in the cellular response to DNA damage and may have implications for its role in suppressing neoplasia [6].
In vivo, MBD4 functions to reduce the mutability of methyl-CpG sites in the genome and mice deticient in MBD4 show increased intestinal tumorigenesis on an Apc(Min/+) background [6].
These properties suggest that MBD4 might function in vivo to minimize the mutability of 5-methylcytosine by removing its deamination product from DNA [7].

Associations of Defb4 with chemical compounds

Mice deficient for MBD4 showed significantly reduced apoptotic responses 6 h following treatment with a range of cytotoxic agents including gamma-irradiation, cisplatin, temozolomide and 5-fluorouracil (5-FU) [6].
MBD4 was originally identified through its methyl binding domain, but has more recently been characterized as a thymine DNA glycosylase that interacts with the mismatch repair (MMR) protein MLH1 [6].
The mammalian protein MBD4 contains a methyl-CpG binding domain and can enzymatically remove thymine (T) or uracil (U) from a mismatched CpG site in vitro [7].

Other interactions of Defb4

Gf C57BL/6 and BALB/c mice expressed significantly different basal levels of mBD3, mBD4, TNF-alpha and IL-12 in gastric tissues; however, gf C57BL/6 and BALB/c mice were equally susceptible to intestinal colonization with C. albicans and had similar fungal burdens in gastric tissues 4 weeks after oral challenge [8].

References

beta-defensin expression in immunocompetent and immunodeficient germ-free and Candida albicans-monoassociated mice. Schofield, D.A., Westwater, C., Balish, E. J. Infect. Dis. (2004) [Pubmed]
beta-Defensin gene expression during the course of experimental tuberculosis infection. Rivas-Santiago, B., Sada, E., Tsutsumi, V., Aguilar-Leon, D., Contreras, J.L., Hernandez-Pando, R. J. Infect. Dis. (2006) [Pubmed]
The base excision repair enzyme MED1 mediates DNA damage response to antitumor drugs and is associated with mismatch repair system integrity. Cortellino, S., Turner, D., Masciullo, V., Schepis, F., Albino, D., Daniel, R., Skalka, A.M., Meropol, N.J., Alberti, C., Larue, L., Bellacosa, A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
Mismatch repair in methylated DNA. Structure and activity of the mismatch-specific thymine glycosylase domain of methyl-CpG-binding protein MBD4. Wu, P., Qiu, C., Sohail, A., Zhang, X., Bhagwat, A.S., Cheng, X. J. Biol. Chem. (2003) [Pubmed]
A novel murine beta -defensin expressed in tongue, esophagus, and trachea. Jia, H.P., Wowk, S.A., Schutte, B.C., Lee, S.K., Vivado, A., Tack, B.F., Bevins, C.L., McCray, P.B. J. Biol. Chem. (2000) [Pubmed]
MBD4 deficiency reduces the apoptotic response to DNA-damaging agents in the murine small intestine. Sansom, O.J., Zabkiewicz, J., Bishop, S.M., Guy, J., Bird, A., Clarke, A.R. Oncogene (2003) [Pubmed]
Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Millar, C.B., Guy, J., Sansom, O.J., Selfridge, J., MacDougall, E., Hendrich, B., Keightley, P.D., Bishop, S.M., Clarke, A.R., Bird, A. Science (2002) [Pubmed]
Divergent chemokine, cytokine and beta-defensin responses to gastric candidiasis in immunocompetent C57BL/6 and BALB/c mice. Schofield, D.A., Westwater, C., Balish, E. J. Med. Microbiol. (2005) [Pubmed]

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