A stress regulatory network for co‐ordinated activation of proteasome expression mediated by yeast heat shock transcription factor

Heat shock transcription factor (HSF) mediates the transcriptional response of eukaryotic cells to heat, infection and inflammation, pharmacological agents, and other stresses. Although genes encoding heat shock proteins (HSPs) are the best characterized targets of HSF, recent genome‐wide localization of Saccharomyces cerevisiae HSF revealed novel HSF targets involved in a wide range of cellular functions. One such target, the RPN4 gene, encodes a transcription factor that directly activates expression of a number of genes encoding proteasome subunits. Here we demonstrate that HSF co‐ordinates a feed‐forward gene regulatory circuit for RPN4 activation. We show that HSF activates expression of PDR3, encoding a multidrug resistance (MDR) transcription factor that also directly activates RPN4 gene expression. We demonstrate that the HSF binding site (HSE) in the RPN4 promoter is primarily responsible for heat‐ or methyl methanesulphonate induction of RPN4, with a minor contribution of Pdr3 binding sites (PDREs), while a Yap1 binding site (YRE) is responsible for RPN4 induction in response to oxidative stress. Furthermore, heat‐induced expression of Rpn4 protein leads to expression of Rpn4 targets at later stages of heat stress, providing a temporal controlling mechanism for proteasome synthesis upon stress conditions that could result in irreversibly damaged proteins. In addition, the overlapping transcriptional regulatory networks involving HSF, Yap1 and Pdr3 suggest a close linkage between stress responses and pleiotropic drug resistance.

[1]  Tokichi Miyakawa,et al.  yAP-1- and yAP-2-mediated, heat shock-induced transcriptional activation of the multidrug resistance ABC transporter genes inSaccharomyces cerevisiae , 2005, Current Genetics.

[2]  Peter K. Sorger,et al.  Yeast heat shock factor contains separable transient and sustained response transcriptional activators , 1990, Cell.

[3]  T. A. Connors.  Alkylating agents. , 1990, Cancer chemotherapy and biological response modifiers.

[4]  G. Owsianik,et al.  Control of 26S proteasome expression by transcription factors regulating multidrug resistance in Saccharomyces cerevisiae , 2002, Molecular microbiology.

[5]  D. Thiele,et al.  A trans-Activation Domain in Yeast Heat Shock Transcription Factor Is Essential for Cell Cycle Progression during Stress , 1999, Molecular and Cellular Biology.

[6]  Ronald W. Davis,et al.  Functional profiling of the Saccharomyces cerevisiae genome , 2002, Nature.

[7]  S. Han,et al.  Implication of a Small GTPase Rac1 in the Activation of c-Jun N-terminal Kinase and Heat Shock Factor in Response to Heat Shock* , 2001, The Journal of Biological Chemistry.

[8]  A. R. Fernandes,et al.  Transcriptional activation of FLR1 gene during Saccharomyces cerevisiae adaptation to growth with benomyl: role of Yap1p and Pdr3p. , 2001, Biochemical and biophysical research communications.

[9]  Richard I. Morimoto,et al.  1 Progress and Perspectives on the Biology of Heat Shock Proteins and Molecular Chaperones , 1994 .

[10]  M. Raymond,et al.  AP1-mediated Multidrug Resistance in Saccharomyces cerevisiae Requires FLR1 Encoding a Transporter of the Major Facilitator Superfamily* , 1997, The Journal of Biological Chemistry.

[11]  R. Morimoto,et al.  Regulation of the Heat Shock Transcriptional Response: Cross Talk between a Family of Heat Shock Factors, Molecular Chaperones, and Negative Regulators the Heat Shock Factor Family: Redundancy and Specialization , 2022 .

[12]  Carl Wu,et al.  Heat shock transcription factors: structure and regulation. , 1995, Annual review of cell and developmental biology.

[13]  M. Resnick,et al.  In vivo site-directed mutagenesis using oligonucleotides , 2001, Nature Biotechnology.

[14]  D. Botstein,et al.  Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF , 2001, Nature.

[15]  Luis A. Martinez,et al.  Heat Shock-Independent Induction of Multidrug Resistance by Heat Shock Factor 1 , 2006, Molecular and Cellular Biology.

[16]  H. Nelson,et al.  A new use for the 'wing' of the 'winged' helix-turn-helix motif in the HSF–DNA cocrystal , 1999, Nature Structural Biology.

[17]  T. Chiba,et al.  Analysis of gene network regulating yeast multidrug resistance by artificial activation of transcription factors: involvement of Pdr3 in salt tolerance. , 2004, Gene.

[18]  N. Vilaboa,et al.  Regulation of Multidrug Resistance 1 (MDR1)/P-glycoprotein Gene Expression and Activity by Heat-Shock Transcription Factor 1 (HSF1)* , 2000, The Journal of Biological Chemistry.

[19]  Nicola J. Rinaldi,et al.  Transcriptional Regulatory Networks in Saccharomyces cerevisiae , 2002, Science.

[20]  Rudy Pandjaitan,et al.  The yeast zinc finger regulators Pdr1p and Pdr3p control pleiotropic drug resistance (PDR) as homo‐ and heterodimers in vivo , 2002, Molecular microbiology.

[21]  K. McEntee,et al.  Multiple independent regulatory pathways control UBI4 expression after heat shock in Saccharomyces cerevisiae , 1999, Molecular microbiology.

[22]  George M. Church,et al.  Regulatory Networks Revealed by Transcriptional Profiling of Damaged Saccharomyces cerevisiae Cells: Rpn4 Links Base Excision Repair with Proteasomes , 2000, Molecular and Cellular Biology.

[23]  N. Mivechi,et al.  Regulatory domain of human heat shock transcription Factor‐2 is not regulated by hemin or heat shock , 1999, Journal of cellular biochemistry.

[24]  S. Jentsch,et al.  Ubiquitin‐conjugating enzymes UBC4 and UBC5 mediate selective degradation of short‐lived and abnormal proteins. , 1990, The EMBO journal.

[25]  L. Sistonen,et al.  Roles of the heat shock transcription factors in regulation of the heat shock response and beyond , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  John Q Trojanowski,et al.  Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs , 2004, Nature Medicine.

[27]  S. Lindquist,et al.  The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. , 1993, Annual review of genetics.

[28]  R Parker,et al.  Identification and comparison of stable and unstable mRNAs in Saccharomyces cerevisiae , 1990, Molecular and cellular biology.

[29]  S. Mangan,et al.  Structure and function of the feed-forward loop network motif , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Tracy Nevitt,et al.  Yeast activator proteins and stress response: an overview , 2004, FEBS letters.

[31]  H. Feldmann,et al.  Rpn4p acts as a transcription factor by binding to PACE, a nonamer box found upstream of 26S proteasomal and other genes in yeast , 1999, FEBS letters.

[32]  V. Iyer,et al.  Genome-Wide Analysis of the Biology of Stress Responses through Heat Shock Transcription Factor , 2004, Molecular and Cellular Biology.

[33]  P. Sorger,et al.  Yeast heat shock factor is an essential DNA-binding protein that exhibits temperature-dependent phosphorylation , 1988, Cell.

[34]  M. Raymond,et al.  Multiple Yap1p-binding Sites Mediate Induction of the Yeast Major Facilitator FLR1 Gene in Response to Drugs, Oxidants, and Alkylating Agents* , 2001, The Journal of Biological Chemistry.

[35]  H. Jungwirth,et al.  Diazaborine Resistance in the Yeast Saccharomyces cerevisiae Reveals a Link between YAP1 and the Pleiotropic Drug Resistance Genes PDR1 andPDR3 * , 1997, The Journal of Biological Chemistry.

[36]  I. Benjamin,et al.  Disruption of Heat Shock Factor 1 Reveals an Essential Role in the Ubiquitin Proteolytic Pathway , 2000, Molecular and Cellular Biology.

[37]  Sue A. Krause,et al.  Protein misfolding and temperature up-shift cause G1 arrest via a common mechanism dependent on heat shock factor in Saccharomyces cerevisiae , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. Goldberg,et al.  Proteasome Inhibitors Cause Induction of Heat Shock Proteins and Trehalose, Which Together Confer Thermotolerance inSaccharomyces cerevisiae , 1998, Molecular and Cellular Biology.

[39]  P. C. Ramos,et al.  Regulatory mechanisms controlling biogenesis of ubiquitin and the proteasome , 2004, FEBS letters.

[40]  C. Jacq,et al.  Genome‐wide studies on the nuclear PDR3‐controlled response to mitochondrial dysfunction in yeast , 2002, FEBS letters.

[41]  Delphine Pflieger,et al.  A Thiol Peroxidase Is an H2O2 Receptor and Redox-Transducer in Gene Activation , 2002, Cell.

[42]  A. Goffeau,et al.  Functional dissection of Pdr1p, a regulator of multidrug resistance in Saccharomyces cerevisiae , 2002, Molecular Genetics and Genomics.

[43]  A. Ciechanover,et al.  The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. , 2002, Physiological reviews.

[44]  S. Shen-Orr,et al.  Network motifs in the transcriptional regulation network of Escherichia coli , 2002, Nature Genetics.

[45]  Kojima.  Structure and function , 2005 .

[46]  R. Morimoto,et al.  Stress-Inducible Cellular Responses , 1996, EXS.

[47]  A. Varshavsky,et al.  RPN4 is a ligand, substrate, and transcriptional regulator of the 26S proteasome: A negative feedback circuit , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[48]  A. Goldberg,et al.  Protein degradation and protection against misfolded or damaged proteins , 2003, Nature.

[49]  D. Botstein,et al.  Genomic expression programs in the response of yeast cells to environmental changes. , 2000, Molecular biology of the cell.

[50]  Claude Jacq,et al.  New Insights into the Pleiotropic Drug Resistance Network from Genome-Wide Characterization of the YRR1 Transcription Factor Regulation System , 2002, Molecular and Cellular Biology.

[51]  M. Reboud-Ravaux.  Proteasome inhibitors. , 2002, Progress in molecular and subcellular biology.

[52]  H. Kowarzyk.  Structure and Function. , 1910, Nature.