The Hsp90 Cochaperone P23 is Essential for Perinatal Survival

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2006 Sep 27

PMID 17000766

Citations 43

Authors

Iwona Grad

Thomas A McKee

Sara M Ludwig

Gary W Hoyle

Patricia Ruiz

Wolfgang Wurst

Thomas Floss

Charles A Miller 3rd

Didier Picard

Affiliations

Soon will be listed here.

Abstract

The functions of molecular chaperones have been extensively investigated biochemically in vitro and genetically in bacteria and yeast. We have embarked on a functional genomic analysis of the Hsp90 chaperone machine in the mouse by disrupting the p23 gene using a gene trap approach. p23 is an Hsp90 cochaperone that is thought to stabilize Hsp90-substrate complexes and, independently, to act as the cytosolic prostaglandin E2 synthase. Gene deletions in budding and fission yeasts and knock-down experiments with the worm have not revealed any clear in vivo requirements for p23. We find that p23 is not essential for overall prenatal development and morphogenesis of the mouse, which parallels the observation that it is dispensable for proliferation in yeast. In contrast, p23 is absolutely necessary for perinatal survival. Apart from an incompletely formed skin barrier, the lungs of p23 null embryos display underdeveloped airspaces and substantially reduced expression of surfactant genes. Correlating with the known function of glucocorticoids in promoting lung maturation and the role of p23 in the assembly of a hormone-responsive glucocorticoid receptor-Hsp90 complex, p23 null fibroblast cells have a defective glucocorticoid response. Thus, p23 contributes a nonredundant, temporally restricted, and tissue-specific function during mouse development.

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References

Stryke D, Kawamoto M, Huang C, Johns S, King L, Harper C . BayGenomics: a resource of insertional mutations in mouse embryonic stem cells. Nucleic Acids Res. 2003; 31(1):278-81. PMC: 165511. DOI: 10.1093/nar/gkg064. View

Richter K, Muschler P, Hainzl O, Buchner J . Coordinated ATP hydrolysis by the Hsp90 dimer. J Biol Chem. 2001; 276(36):33689-96. DOI: 10.1074/jbc.M103832200. View

Hansen J, Floss T, Van Sloun P, Fuchtbauer E, Vauti F, Arnold H . A large-scale, gene-driven mutagenesis approach for the functional analysis of the mouse genome. Proc Natl Acad Sci U S A. 2003; 100(17):9918-22. PMC: 187885. DOI: 10.1073/pnas.1633296100. View

Felts S, Toft D . p23, a simple protein with complex activities. Cell Stress Chaperones. 2003; 8(2):108-13. PMC: 514861. DOI: 10.1379/1466-1268(2003)008<0108:paspwc>2.0.co;2. View

Wochnik G, Young J, Schmidt U, Holsboer F, Hartl F, Rein T . Inhibition of GR-mediated transcription by p23 requires interaction with Hsp90. FEBS Lett. 2004; 560(1-3):35-8. DOI: 10.1016/S0014-5793(04)00066-3. View

Cole T, Solomon N, van Driel R, Monk J, Bird D, Richardson S . Altered epithelial cell proportions in the fetal lung of glucocorticoid receptor null mice. Am J Respir Cell Mol Biol. 2003; 30(5):613-9. DOI: 10.1165/rcmb.2003-0236OC. View

DeMello D . Pulmonary pathology. Semin Neonatol. 2004; 9(4):311-29. DOI: 10.1016/j.siny.2003.12.001. View

Marks R . The stratum corneum barrier: the final frontier. J Nutr. 2004; 134(8 Suppl):2017S-2021S. DOI: 10.1093/jn/134.8.2017S. View

Heymann M, Rudolph A, Silverman N . Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N Engl J Med. 1976; 295(10):530-3. DOI: 10.1056/NEJM197609022951004. View

10.

Odom M, Snyder J, Mendelson C . Adenosine 3',5'-monophosphate analogs and beta-adrenergic agonists induce the synthesis of the major surfactant apoprotein in human fetal lung in vitro. Endocrinology. 1987; 121(3):1155-63. DOI: 10.1210/endo-121-3-1155. View

11.

Picard D, Yamamoto K . Two signals mediate hormone-dependent nuclear localization of the glucocorticoid receptor. EMBO J. 1987; 6(11):3333-40. PMC: 553788. DOI: 10.1002/j.1460-2075.1987.tb02654.x. View

12.

Acarregui M, Snyder J, Mitchell M, Mendelson C . Prostaglandins regulate surfactant protein A (SP-A) gene expression in human fetal lung in vitro. Endocrinology. 1990; 127(3):1105-13. DOI: 10.1210/endo-127-3-1105. View

13.

Aszterbaum M, Feingold K, Menon G, Williams M . Glucocorticoids accelerate fetal maturation of the epidermal permeability barrier in the rat. J Clin Invest. 1993; 91(6):2703-8. PMC: 443334. DOI: 10.1172/JCI116509. View

14.

Johnson J, Toft D . A novel chaperone complex for steroid receptors involving heat shock proteins, immunophilins, and p23. J Biol Chem. 1994; 269(40):24989-93. View

15.

Muglia L, Jacobson L, Dikkes P, Majzoub J . Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature. 1995; 373(6513):427-32. DOI: 10.1038/373427a0. View

16.

Imakado S, Bickenbach J, Bundman D, Rothnagel J, Attar P, Wang X . Targeting expression of a dominant-negative retinoic acid receptor mutant in the epidermis of transgenic mice results in loss of barrier function. Genes Dev. 1995; 9(3):317-29. DOI: 10.1101/gad.9.3.317. View

17.

Cole T, Blendy J, Monaghan A, Krieglstein K, Schmid W, Aguzzi A . Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. 1995; 9(13):1608-21. DOI: 10.1101/gad.9.13.1608. View

18.

Hutchison K, Stancato L, Johnson J, Krishna P, Toft D, Pratt W . The 23-kDa acidic protein in reticulocyte lysate is the weakly bound component of the hsp foldosome that is required for assembly of the glucocorticoid receptor into a functional heterocomplex with hsp90. J Biol Chem. 1995; 270(32):18841-7. DOI: 10.1074/jbc.270.32.18841. View

19.

Clark J, Wert S, Bachurski C, STAHLMAN M, Stripp B, Weaver T . Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice. Proc Natl Acad Sci U S A. 1995; 92(17):7794-8. PMC: 41232. DOI: 10.1073/pnas.92.17.7794. View

20.

Freeman B, Morimoto R . The human cytosolic molecular chaperones hsp90, hsp70 (hsc70) and hdj-1 have distinct roles in recognition of a non-native protein and protein refolding. EMBO J. 1996; 15(12):2969-79. PMC: 450238. View