Identification and characterization of HAP4: a third component of the CCAAT-bound HAP2/HAP3 heteromer.

Forsburg, Susan L.; Guarente, Leonard

doi:10.1101/gad.3.8.1166

Cited by 409 publications

(362 citation statements)

References 70 publications

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“…Finally, the HAP elements are also involved in regulation of HXT5 expression. Activity of the Hap2/3/4/5p complex, which probably binds to the HAP elements in the HXT5 promoter, is dependent on the Hap4p subunit, whose transcription is repressed by glucose (Brons et al, 2002;DeRisi et al, 1997;Forsburg and Guarente, 1989). Thus, the HAP elements may also contribute to HXT5 expression specifically when glucose is absent, i.e.…”

Section: Discussionmentioning

confidence: 99%

HXT5 expression is under control of STRE and HAP elements in the HXT5 promoter

Verwaal

Arako

Kapur

et al. 2004

Yeast

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Hexose transporter (Hxt) proteins transport glucose across the plasma membrane in the yeast Saccharomyces cerevisiae. Recently, we have shown that expression of HXT5 is regulated by the growth rate of the cells. Because gene expression is regulated by binding of specific transcription factors to regulatory elements in the promoters of genes, the presence of putative regulatory elements in the promoter of HXT5 was determined by computer-assisted analysis. This revealed the presence of two putative stress-responsive elements (STREs), one putative post-diauxic shift (PDS) element and two putative Hap2/3/4/5p (HAP) complex binding elements. The involvement of these elements was studied by using mutations in a HXT5 promoter-LacZ fusion construct. Growth during various conditions that result in low growth rates of yeast cells revealed that the STRE most proximal to the translation initiation site seemed to be involved in particular in regulation of HXT5 expression during growth at decreased growth rates. In addition, the HAP elements seemed to be required during growth on non-fermentable carbon sources. The PDS element and, to a lesser extent, the other STRE showed particular involvement in regulation of HXT5 expression during growth on ethanol. Finally, it was shown that the PKA pathway, which is known to be involved in expression of STRE-regulated genes, was also involved in regulation of HXT5 expression. A possible mechanism by which expression of HXT5 could be regulated by the transcriptional regulatory elements in the promoter is discussed.

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Section: Discussionmentioning

confidence: 99%

HXT5 expression is under control of STRE and HAP elements in the HXT5 promoter

Verwaal

Arako

Kapur

et al. 2004

Yeast

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“…The main transcriptional regulator of this induction is thought to be the heterotrimeric transcription-activation complex HAP2/3/4. The genes for the proteins of this complex were isolated via a selection procedure that exploited the ability of the subunits of the complex to bind to UASup1 of the CYC1 gene and to activate transcription (Pinkham and Guarente 1985;Hahn et al 1988;Forsburg and Guarente 1989). Based on in vitro mobility-shift experiments, Olesen et al (1987) concluded that HAP2 and HAP3 bind to the DNA in an interdependent manner.…”

Section: Introductionmentioning

confidence: 99%

“…Based on in vitro mobility-shift experiments, Olesen et al (1987) concluded that HAP2 and HAP3 bind to the DNA in an interdependent manner. HAP4 protein does not bind DNA directly, but augments the binding of HAP2 and HAP3 (Forsburg and Guarente 1989). Mutations in any of the three HAP genes lead to a non-functional complex, with a consequently diminished induction of genes coding for mitochondrial proteins.…”

Section: Introductionmentioning

confidence: 99%

“…In S. cerevisiae the HAP2 and HAP3 genes are expressed constitutively at a low level, whereas the expression of the HAP4 gene is glucose repressible. This suggests that HAP4 is a key regulator of the HAP2/3/4 complex in its response to carbon source (Forsburg and Guarente 1989). Genes corresponding to HAP2 and HAP3 have been isolated from a number of organisms (Chodosh et al 1988a;Hooft van Huijsduijnen et al 1990;Maity et al 1990;Vuorio et al 1990;Olesen et al 1991;Li et al 1992b).…”

Section: Introductionmentioning

confidence: 99%

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Sequence of the HAP3 transcription factor of Kluyveromyces lactis predicts the presence of a novel 4-cysteine zinc-finger motif

Mulder¹,

Scholten²,

Boer³

et al. 1994

Molec. Gen. Genet.

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Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Abstract The Kluyveromyces lactis homologue of the Saecharomyces cerevisiae HAP3 gene was isolated by functional complementation of the respiratorydeficient phenotype of the S. cerevisiae hap3::HIS4 strain SHY40. The K1HAP3 gene encodes a protein of 205 amino acids, of which the central B-domain of 90 residues is highly homologous to HAP3 counterparts of S. cerevisiae and higher eukaryotes. The protein contains a novel 4-cysteine zinc-finger motif and we propose by analogy that all other homologous HAP3 proteins contain the same motif, with the position containing the third cysteine being occupied by a serine residue. In contrast to the situation in S. cerevisiae, disruption of the K1HAP3 gene in K. lactis does not result in a respiratory-deficient phenotype and the growth of the null strain is indistinguishable from wild type. There is also no effect on the expression of the carbon source-regulated KICYC1 gene, suggesting either a different role for the HAP2/3/4 complex, or the existence of a different mechanism of carbon source regulation. Sequence verification of the S. cerevisiae HAP3 locus reveals that, just as in K. lactis, a long open reading frame (ORF) is present upstream of the HAP3 gene. These highly homologous ORFs are predicted to have at least eight membrane-spanning fragments, but do not show significant homology to any known sequence present in databases. The ScORFX gene is transcribed in the opposite direction to ScHAP3, but, in contrast to an earlier report by Hahn et al. (1988), the transcripts of the two genes do not overlap. The model proposed by these authors, in which the ScHAP3 gene is regulated by an anti-sense non-coding mRNA, is therefore not correct.

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“…In the cdc25-10 mutant, the glucose-responsive cAMP-activated PKA activity is downregulated, thereby increasing life span (Lin et al 2000). Hap4 is a component of the Hap complex that binds to the consensus sequences CCAAT and increases the transcription of many genes involved in mitochondrial metabolism (Forsburg and Guarente 1989). Overexpressing Hap4 has been shown to induce a metabolic shift toward respiration and extend life span (Lin et al 2002).…”

Section: A Functional Nadh Shuttle Is Required For Multiple Genetic Mmentioning

confidence: 99%

The malate–aspartate NADH shuttle components are novel metabolic longevity regulators required for calorie restriction-mediated life span extension in yeast

Easlon¹,

Tsang²,

Skinner³

et al. 2008

Genes Dev.

133

118

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Recent studies suggest that increased mitochondrial metabolism and the concomitant decrease in NADH levels mediate calorie restriction (CR)-induced life span extension. The mitochondrial inner membrane is impermeable to NAD (nicotinamide adenine dinucleotide, oxidized form) and NADH, and it is unclear how CR relays increased mitochondrial metabolism to multiple cellular pathways that reside in spatially distinct compartments. Here we show that the mitochondrial components of the malate-aspartate NADH shuttle (Mdh1 [malate dehydrogenase] and Aat1 [aspartate amino transferase]) and the glycerol-3-phosphate shuttle (Gut2, glycerol-3-phosphate dehydrogenase) are novel longevity factors in the CR pathway in yeast. Overexpressing Mdh1, Aat1, and Gut2 extend life span and do not synergize with CR. Mdh1 and Aat1 overexpressions require both respiration and the Sir2 family to extend life span. The mdh1⌬aat1⌬ double mutation blocks CR-mediated life span extension and also prevents the characteristic decrease in the NADH levels in the cytosolic/nuclear pool, suggesting that the malate-aspartate shuttle plays a major role in the activation of the downstream targets of CR such as Sir2. Overexpression of the NADH shuttles may also extend life span by increasing the metabolic fitness of the cells. Together, these data suggest that CR may extend life span and ameliorate age-associated metabolic diseases by activating components of the NADH shuttles.[Keywords: Calorie restriction (CR); Sir2; aging; NADH shuttles; respiration; metabolism] Supplemental material is available at http://www.genesdev.org.

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Identification and characterization of HAP4: a third component of the CCAAT-bound HAP2/HAP3 heteromer.

Cited by 409 publications

References 70 publications

HXT5 expression is under control of STRE and HAP elements in the HXT5 promoter

HXT5 expression is under control of STRE and HAP elements in the HXT5 promoter

Sequence of the HAP3 transcription factor of Kluyveromyces lactis predicts the presence of a novel 4-cysteine zinc-finger motif

The malate–aspartate NADH shuttle components are novel metabolic longevity regulators required for calorie restriction-mediated life span extension in yeast

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