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Molecular and Cellular Biology, February 2006, p. 883-897, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.883-897.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mxr1p, a Key Regulator of the Methanol Utilization Pathway and Peroxisomal Genes in Pichia pastoris

Geoffrey Paul Lin-Cereghino,1,2,{dagger} Laurie Godfrey,1 Bernard J. de la Cruz,2 Sabrina Johnson,1,{dagger} Samone Khuongsathiene,1,{ddagger} Ilya Tolstorukov,2 Mingda Yan,3 Joan Lin-Cereghino,1,2,{dagger} Marten Veenhuis,4 Suresh Subramani,3 and James M. Cregg1,2*

Department of Biochemistry and Molecular Biology, Oregon Graduate Institute of Science and Technology, 2000 N.W. Walker Road, Beaverton, Oregon 97006,1 Keck Graduate Institute of Applied Life Sciences, 535 Watson Drive, Claremont, California 91711,2 Section of Molecular Biology, Division of Biological Sciences, University of California at San Diego, La Jolla, California 92093,3 Department of Eukaryotic Microbiology, University of Groningen, 9751 NN Haren, The Netherlands4

Received 25 May 2005/ Returned for modification 26 July 2005/ Accepted 24 October 2005

Growth of the yeast Pichia pastoris on methanol induces the expression of genes whose products are required for its metabolism. Three of the methanol pathway enzymes are located in an organelle called the peroxisome. As a result, both methanol pathway enzymes and proteins involved in peroxisome biogenesis (PEX proteins) are induced in response to this substrate. The most highly regulated of these genes is AOX1, which encodes alcohol oxidase, the first enzyme of the methanol pathway, and a peroxisomal enzyme. To elucidate the molecular mechanisms responsible for methanol regulation, we identify genes required for the expression of AOX1. Mutations in one gene, named MXR1 (methanol expression regulator 1), result in strains that are unable to (i) grow on the peroxisomal substrates methanol and oleic acid, (ii) induce the transcription of AOX1 and other methanol pathway and PEX genes, and (iii) form normal-appearing peroxisomes in response to methanol. MXR1 encodes a large protein with a zinc finger DNA-binding domain near its N terminus that has similarity to Saccharomyces cerevisiae Adr1p. In addition, Mxr1p is localized to the nucleus in cells grown on methanol or other gluconeogenic substrates. Finally, Mxr1p specifically binds to sequences upstream of AOX1. We conclude that Mxr1p is a transcription factor that is necessary for the activation of many genes in response to methanol. We propose that MXR1 is the P. pastoris homologue of S. cerevisiae ADR1 but that it has gained new functions and lost others through evolution as a result of changes in the spectrum of genes that it controls.

* Corresponding author. Mailing address: Keck Graduate Institute of Applied Life Sciences, 535 Watson Drive, Claremont, CA 91711. Phone: (909) 607-8562. Fax: (909) 607-8086. E-mail: James_Cregg{at}kgi.edu.

{dagger} Present address: Department of Biological Sciences, University of the Pacific, Stockton, CA 95211.

{ddagger} Present address: Department of Medical Informatics, Oregon Health Sciences University, Portland, OR 97201.

Molecular and Cellular Biology, February 2006, p. 883-897, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.883-897.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hartner, F. S., Ruth, C., Langenegger, D., Johnson, S. N., Hyka, P., Lin-Cereghino, G. P., Lin-Cereghino, J., Kovar, K., Cregg, J. M., Glieder, A. (2008). Promoter library designed for fine-tuned gene expression in Pichia pastoris. Nucleic Acids Res 36: e76-e76 [Abstract] [Full Text]  
  • Sasano, Y., Yurimoto, H., Yanaka, M., Sakai, Y. (2008). Trm1p, a Zn(II)2Cys6-Type Transcription Factor, Is a Master Regulator of Methanol-Specific Gene Activation in the Methylotrophic Yeast Candida boidinii. Eukaryot Cell 7: 527-536 [Abstract] [Full Text]  
  • Kranthi, B. V., Balasubramanian, N., Rangarajan, P. N. (2006). Isolation of a single-stranded DNA-binding protein from the methylotrophic yeast, Pichia pastoris and its identification as zeta crystallin. Nucleic Acids Res 34: 4060-4068 [Abstract] [Full Text]  


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