Chapter 25 : Multidrug Resistance Transcriptional Regulatory Networks in

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species are an important cause of both mucosal and invasive opportunistic infections among immuno-compromised patient populations, such as cancer patients receiving cytotoxic chemotherapy, solid-organ and bone marrow transplant patients receiving immunosuppressant therapy, and patients infected with human immunodeficiency virus (HIV) and suffering from AIDS. Moreover, recent reports have highlighted a paradoxical OPC infection rate of 30% in HIV-infected individuals who have shown improvements in CD4 counts and have been classified as ''immune reconstituted''. This chapter focuses on the transcriptional regulation of azole antifungal resistance as well as transcriptional regulators that influence azole susceptibility in species. Much of our understanding of azole antifungal resistance in species has been greatly facilitated by the study of the pleiotropic drug resistance phenotype in , which is largely driven by ATP-binding cassette (ABC) transporters such as Pdr5p. In a study to generate a more global assessment of Ndt80p, it was found that Ndt80p was bound to the promoters of many genes previously identified as being associated with azole resistance, including the ABC transporter genes , , and ; the MFS transporter genes , , , and ; the flippase genes and ; and other azole resistance-associated genes, , , and .

Citation: Rogers P, Barker K. 2012. Multidrug Resistance Transcriptional Regulatory Networks in , p 403-416. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch25
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Image of FIGURE 1

Promoter regions containing known response elements of the , and genes. Each binding region is shaded or patterned according to the type of response element, the 5‵ boundary of the ORFs is indicated by the bent arrow, and the ORFs are indicated by the shaded arrow. (A) The gene promoter contains MSEs putatively bound by Ndt80p ( ), SREs shown to be progesterone responsive (SRE1) or progesterone- and estradiol-responsive (SRE2) ( ), and a DRE putatively bound by Tac1p ( ). (B) The gene promoter contains an HRE and BRE ( ), which both overlap with constitutive activation regions 2 and 3, respectively ( ). An additional region (region 1) was also identified by Hiller et al. ( ). The MDRE, putatively bound by Mcm1p ( ), is contained within the boundaries of the BRE. The -butyl-hydroperoxide (T-BHP)-responsive and benomyl (BEN)-responsive elements ( ) are found within regions 2 and 1, respectively. (C) The gene promoter contains two SREs, presumably bound by Upc2p ( ), and an azole response element (ARE) ( ). doi:10.1128/9781555817176.ch25.f1

Citation: Rogers P, Barker K. 2012. Multidrug Resistance Transcriptional Regulatory Networks in , p 403-416. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch25
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Image of FIGURE 2

Representation of gain-of-function mutations identified to date in Tac1p, Mrr1p, Upc2p, and CgPdr1p. Each protein is displayed from N to C terminus (left to right). The shaded and patterned boxes correspond to functional motifs defined as follows: ZnCys zinc finger DNA-binding domain in medium gray boxes, activation domain of Tac1p ( ) and of CgPdr1p ( ) in black boxes, putative NLS of Upc2p and of CgPdr1p in horizontally hatched boxes, and xenobiotic binding domain of CgPdr1p ( ) in light gray boxes. Only gain-of-function mutations that have been experimentally verified are shown. The Tac1p mutations were originally described by Coste et al. ( ) and Znaidi et al. ( ), the Mrr1p mutations were originally described by Morschhäuser et al. ( ) and Dunkel et al. ( ), the Upc2p mutations were originally described by Dunkel et al. ( ) and Heilmann et al. ( ), and the Pdr1p mutations were originally described by Ferrari et al. ( ), Torelli et al. ( ), Tsai et al. ( ), Vermitsky and Edlind ( ), and K. E. Caudle et al. (unpublished data). doi:10.1128/9781555817176.ch25.f2

Citation: Rogers P, Barker K. 2012. Multidrug Resistance Transcriptional Regulatory Networks in , p 403-416. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch25
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