ARNT isoforms differentially regulate cancer cell growth through a p53-dependent mechanism.
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Aryl hydrocarbon receptor nuclear translocator (ARNT) is an important player in xenobiotic and hypoxic responses. In addition to this, my mentor has shown that ARNT is an integral cofactor of NF-kB signaling. However, these initial observations of ARNT-mediated NF-kB modulation were based on simultaneous suppression of the two ARNT isoforms, isoform 1 and 3, and therefore precluded the isolated examination of each isoform’s function. We show here that lymphoid malignancies exhibit higher levels of ARNT isoform 1 compared to ARNT isoform 3. However, normal T and B lymphocytes are seen to harbor equal levels of ARNT isoform 1 and 3. We hypothesize that the increase in ARNT isoform 1 is necessary for the growth of these cancer cells as suppression of isoform 1 resulted in S-phase cell cycle arrest. These findings reveal that ARNT isoform 1 potentiates cell growth by antagonizing a p53 cell cycle inhibitory mechanism and this further suggests that ARNT targeted therapies would benefit chemotherapy regimens.