Transcriptionally Active Heterodimer Formation of an Arnt-like PAS Protein, Arnt3, with HIF-1a, HLF, and Clock

Takahata, Sho; Sogawa, Kazuhiro; Kobayashi, Akira; Ema, Masatsugu; Mimura, Junsei; Ozaki, Nobuhiro; Fujii‐Kuriyama, Yoshiaki

doi:10.1006/bbrc.1998.9012

Cited by 134 publications

(94 citation statements)

References 38 publications

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“…1. It is of much interest to note that the full length mArnt3 showed no enhancing effect on the luciferase expression, in consistence with our previous results (Takahata et al 1998), but in sharp contrast with the results from the yeast system. The expressions of these various fragments of the effector proteins were more or less constant and were not so variable as to explain the variations in their transactivation activities (Fig.…”

Section: Activation Domains Of Marnt3 and Mclock De®ned By The One-hysupporting

confidence: 83%

“…The blunt-ended BamHI/HindIII fragment of pBSK-mClock (Takahata et al 1998) for amino acids 1±855, NcoI for 1±559, XbaI for 435±855 were inserted into the appropriate sites of pEFBOS-GAL4DBD. Construction of expression plasmids coding for GAL4DBD-Arnt3 chimeric proteins was performed as previously described (Takahata et al 1998).…”

Section: Construction Of Plasmidsmentioning

confidence: 99%

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Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3

et al. 2000

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Section: Activation Domains Of Marnt3 and Mclock De®ned By The One-hysupporting

confidence: 83%

Section: Construction Of Plasmidsmentioning

confidence: 99%

Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3

et al. 2000

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“…It has been demonstrated previously that the members of PAS-domain family of proteins can form complexes in various combinations (Swanson et al 1995;Hogenesch et al 1997Hogenesch et al , 1998Takahata et al 1998). We therefore checked whether other members of the PAS domain proteins family could dimerize with either CLOCK or BMAL1 and induce similar posttranslational events.…”

Section: Direct Clock/bmal1 Interaction Through Pas Domain Is Necessamentioning

confidence: 98%

BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system

Kondratov¹,

Chernov²,

Kondratova³

et al. 2003

Genes Dev.

225

227

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Mammalian CLOCK and BMAL1 are two members of bHLH-PAS-containing family of transcription factors that represent the positive elements of circadian autoregulatory feedback loop. In the form of a heterodimer, they drive transcription from E-box enhancer elements in the promoters of responsive genes. We have examined abundance, posttranslational modifications, cellular localization of endogenous and ectopically expressed CLOCK and BMAL1 proteins. Nuclear/cytoplasm distribution of CLOCK was found to be under circadian regulation. Analysis of subcellular localization of CLOCK in embryo fibroblasts of mice carrying different germ-line circadian mutations showed that circadian regulation of nuclear accumulation of CLOCK is BMAL1-dependent. Formation of CLOCK/BMAL1 complex following ectopic coexpression of both proteins is followed by their codependent phosphorylation, which is tightly coupled to CLOCK nuclear translocation and degradation. This binding-dependent coregulation is specific for CLOCK/BMAL1 interaction, as no other PAS domain protein that can form a complex with either CLOCK or BMAL1 was able to induce similar effects. Importantly, all posttranslational events described in our study are coupled with active transactivation complex formation, which argues for their significant functional role. Altogether, these results provide evidence for an additional level of circadian system control, which is based on regulation of transcriptional activity or/and availability of CLOCK/BMAL1 complex.[Keywords: Circadian rhythm; CLOCK/BMAL1 complex; transcriptional activation; phosphorylation; nuclear entry] Supplemental material is available at www.genesdev.org.

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“…ARNT 2 is closely related to ARNT and, although it is primarily expressed in neural tissues (25), is capable of heterodimerizing with HIF and inducing transcription (26,27). ARNT 3 has less homology to ARNT and ARNT2 (28) and is reported to stimulate significantly less HIF-dependent transcription than ARNT (28,29), while another report demonstrates a complete inability of ARNT3 to associate with HIF (27). To test whether other ARNT-related family members could similarly up-regulate HIF protein, 786-O cells were transfected with HIF and either ARNT, ARNT 2, or ARNT 3.…”

Section: The Pas Domain Of Hif Associates With Hsp90 and Confersmentioning

confidence: 99%

Aryl Hydrocarbon Nuclear Translocator (ARNT) Promotes Oxygen-independent Stabilization of Hypoxia-inducible Factor-1α by Modulating an Hsp90-dependent Regulatory Pathway

Isaacs

Jung

Neckers

2004

Journal of Biological Chemistry

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Hypoxia-inducible factor-1 (HIF-1) is a potent cellular survival factor contributing to tumorigenesis in a broad range of cancers. The functional transcription factor exists as a heterodimeric complex consisting of HIF-1␣ and the aryl hydrocarbon receptor nuclear translocator (ARNT). Association of HIF-1 with ARNT is required for its activity; however, no other role has been ascribed to this interaction. We demonstrated previously that pharmacologic inhibition of Hsp90 by geldanamycin (GA) impairs HIF transcription and promotes VHL (Von Hippel-Lindau)-independent degradation of the protein, thus implicating Hsp90 as an essential interacting partner for HIF. In this study, we further explore the physiological role for Hsp90 in HIF function. We establish that the PAS (Per-ARNT-Sim) domain of HIF is required both to promote association with Hsp90 and confer sensitivity to GA. Coincidentally, this domain also associates with ARNT. Overexpression of ARNT in a VHLdeficient background resulted in substantially increased HIF-1 protein concomitant with increased protein stability. Conversely, down-regulation of endogenous ARNT protein by RNA interference decreased the steady-state HIF protein. ARNT-mediated stabilization of HIF is specific for the Hsp90-dependent pathway, as ARNT was unable to protect HIF from VHL-mediated degradation. We establish that the ability of ARNT to up-regulate HIF and diminish HIF sensitivity to GA is due to its ability to compete for the Hsp90 binding site on HIF. These data elucidate novel functions for ARNT and Hsp90 in regulating HIF function and further illustrate that cofactor association may significantly impact upon the sensitivity of Hsp90 clients to chaperone inhibitors.

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Transcriptionally Active Heterodimer Formation of an Arnt-like PAS Protein, Arnt3, with HIF-1a, HLF, and Clock

Cited by 134 publications

References 38 publications

Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3

Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3

BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system

Aryl Hydrocarbon Nuclear Translocator (ARNT) Promotes Oxygen-independent Stabilization of Hypoxia-inducible Factor-1α by Modulating an Hsp90-dependent Regulatory Pathway

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