It has been found to be expressed in all tissues analyzed It is

It has been found to be expressed in all tissues analyzed. It is present in the cyto sol and in the nucleus. Its transcriptional activity is the most selleckchem studied, especially its regulation of detoxification en zymes such as cytochrome P450. The RAR RXR and AhR pathways are known to crosstalk. For example, they compete for the silencing mediator of retinoid and thyroid receptors protein. Inhibitors,Modulators,Libraries Consistent with various molecular indications of crosstalk, the two pathways can give rise to similar pathologies. For example, teratogenic effects such as cleft palate and hydronephrosis can be in duced by retinoids and also by an AhR agonist, 2,3,7, 8 tetrachlorodibenzo p dioxin. They can also contribute to common developmental processes. For ex ample, in fish, RA and its receptors are required both for AhR transcription and embryonic development of blood vessels and bones.

AhR can thus regulate RA effects, as well as vice versa, but the mechanisms are not Inhibitors,Modulators,Libraries well understood. Recently, several papers reported that the AhR gene can act as a tumor suppressor in the absence of xenobi otics. AhR has been shown to have a role in propelling breast cancer and liver cancer cell differenti ation. AhR knockout mice injected with the liver tumor initiator diethylnitrosamine Inhibitors,Modulators,Libraries have increased liver tumor formation and growth, with increased cell prolif eration, inflammatory cytokine expression and DNA damage compared to wild type mice treated with DEN or untreated mice. Moreover, the AhR knockout mice have increased cecal carcinogenesis. Certain AhR antagonists promote hematopoietic stem cell pro liferation.

The full molecular mechanism of AhR dependent tumor suppressing activity is far from being elucidated, however, some details are emerging. Histor Inhibitors,Modulators,Libraries ically, the most studied function of AhR is its transcrip tional activity elicited by xenobiotics. Recently Inhibitors,Modulators,Libraries it has become apparent that xenobiotics and endogenous li gands have different transcriptional properties, leading to opposite outcomes. For example, it was proposed that transient AhR transcriptional activity, characteris tic of endogenous ligands such as 6 Formylindolo carbazole, is essential for the role of AhR in stem progenitor cell homeostasis, whereas prolonged transcriptional activation is induced by exogenous li gands, such as TCDD, a well known carcinogen.

The more recently emerging role of AhR in protein deg radation via selleck chem CUL4B AhR mediated ubiquitylation and consequently cancer suppression is also of potentially related significance. While the mechanisms are not yet clear, it appears that depending on the model system and on the ligand used, AhR can drive transformation or differentiation. We have previously shown that AhR propels RA induced differentiation of human myeloblastic leukemia cells by downregulating the nuclear transcription factor, Oct4. Oct4 is a Yamanaka Thomson factor control ling stem cells. This process depends on MAPK signaling.

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