Am. J. Respir. Cell Mol. Biol., Volume 18, Number 3, March, 1998 297-306

RAPID COMMUNICATION
Pneumocystis carinii Contains a Functional Cell-division-cycle Cdc2 Homologue

Charles F. Thomas Jr., Robert A. Anders, Michael P. Gustafson, Edward B. Leof, and Andrew H. Limper

Division of Pulmonary, Critical Care and Internal Medicine, and Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota

Pneumocystis carinii causes life-threatening pneumonia in immunocompromised patients. The inability to culture P. carinii has hampered basic investigations of the organism's life cycle, limiting the development of new therapies directed against it. Recent investigations indicate that P. carinii is a fungus phylogenetically related to other ascomycetes such as Schizosaccharomyces pombe. The cell cycles of S. pombe and homologous fungi are carefully regulated by cell-division-cycle molecules (cdc), particularly cell-division-cycle 2 (Cdc2), a serine-threonine kinase with essential activity at the G₁ restriction point and for entry into mitosis. Antibodies to the proline-serine-threonine-alanine-isoleucine-arginine (PSTAIR) amino-acid sequence conserved in Cdc2 proteins specifically precipitated, from P. carinii extracts, a molecule with kinase activity consistent with a Cdc2-like protein. Cdc2 molecules exhibit differential activity throughout the life cycle of the organisms in which they occur. In accord with this, the P. carinii Cdc2 showed greater specific activity in P. carinii trophic forms (trophozoites) than in spore-case forms (cysts). In addition, complete genomic and complementary DNA (cDNA) sequences of P. carinii Cdc2 were cloned and found to be most closely homologus to the corresponding sequences of other pathogenic fungi. The function of P. carinii cdc2 cDNA was further documented through its ability to complement the DNA of mutant strains of S. pombe with temperature-sensitive deficiencies in Cdc2 activity. The P. carinii cdc2 cDNA restored normal Cdc2 function in these mutant strains of S. pombe, and promoted fungal proliferation. These studies represent the first molecular analysis of the cell-cycle-regulatory machinery in P. carinii. Further understanding of P. carinii's life cycle promises novel insights for preventing and treating the intractable infection it causes in immunocompromised patients.

This article has been cited by other articles:

				J. W. Burgess, T. J. Kottom, and A. H. Limper Pneumocystis carinii Exhibits a Conserved Meiotic Control Pathway Infect. Immun., January 1, 2008; 76(1): 417 - 425. [Abstract] [Full Text] [PDF]

				L. Huang, A. Morris, A. H. Limper, J. M. Beck, and on behalf of the ATS Pneumocystis Workshop Partici An Official ATS Workshop Summary: Recent Advances and Future Directions in Pneumocystis Pneumonia (PCP) Proceedings of the ATS, November 1, 2006; 3(8): 655 - 664. [Abstract] [Full Text] [PDF]

				T. J. Kottom and A. H. Limper Pneumocystis carinii Cell Wall Biosynthesis Kinase Gene CBK1 Is an Environmentally Responsive Gene That Complements Cell Wall Defects of cbk-Deficient Yeast Infect. Immun., August 1, 2004; 72(8): 4628 - 4636. [Abstract] [Full Text] [PDF]

				C. F. Thomas Jr. and A. H. Limper Pneumocystis Pneumonia N. Engl. J. Med., June 10, 2004; 350(24): 2487 - 2498. [Full Text] [PDF]

				T. J. Kottom, J. R. Kohler, C. F. Thomas Jr., G. R. Fink, and A. H. Limper Lung Epithelial Cells and Extracellular Matrix Components Induce Expression of Pneumocystis carinii STE20, a Gene Complementing the Mating and Pseudohyphal Growth Defects of ste20 Mutant Yeast Infect. Immun., November 1, 2003; 71(11): 6463 - 6471. [Abstract] [Full Text] [PDF]

				I. J. Morales, P. K. Vohra, V. Puri, T. J. Kottom, A. H. Limper, and C. F. Thomas Jr. Characterization of a Lanosterol 14{alpha}-Demethylase from Pneumocystis carinii Am. J. Respir. Cell Mol. Biol., August 1, 2003; 29(2): 232 - 238. [Abstract] [Full Text] [PDF]

				S.-J. Yong, Z. Vuk-Pavlovic, J. E. Standing, E. C. Crouch, and A. H. Limper Surfactant Protein D-Mediated Aggregation of Pneumocystis carinii Impairs Phagocytosis by Alveolar Macrophages Infect. Immun., April 1, 2003; 71(4): 1662 - 1671. [Abstract] [Full Text]

				T. J. Kottom, C. F. Thomas Jr., and A. H. Limper Characterization of Pneumocystis carinii PHR1, a pH-Regulated Gene Important for Cell Wall Integrity J. Bacteriol., December 1, 2001; 183(23): 6740 - 6745. [Abstract] [Full Text] [PDF]

				T. J. Kottom, C. F. Thomas Jr., K. K. Mubarak, E. B. Leof, and A. H. Limper Pneumocystis carinii Uses a Functional Cdc13 B-Type Cyclin Complex during Its Life Cycle Am. J. Respir. Cell Mol. Biol., June 1, 2000; 22(6): 722 - 731. [Abstract] [Full Text]

				R. Vassallo, J. E. Standing, and A. H. Limper Isolated Pneumocystis carinii Cell Wall Glucan Provokes Lower Respiratory Tract Inflammatory Responses J. Immunol., April 1, 2000; 164(7): 3755 - 3763. [Abstract] [Full Text] [PDF]

				C. F. Thomas Jr., E. B. Leof, and A. H. Limper Analysis of Pneumocystis carinii Introns Infect. Immun., November 1, 1999; 67(11): 6157 - 6160. [Abstract] [Full Text] [PDF]

				C. F. Thomas Jr., T. J. Kottom, E. B. Leof, and A. H. Limper Characterization of a mitogen-activated protein kinase from Pneumocystis carinii Am J Physiol Lung Cell Mol Physiol, July 1, 1998; 275(1): L193 - L199. [Abstract] [Full Text] [PDF]

				T. J. Kottom and A. H. Limper Cell Wall Assembly by Pneumocystis carinii. EVIDENCE FOR A UNIQUE Gsc-1 SUBUNIT MEDIATING beta -1,3-GLUCAN DEPOSITION J. Biol. Chem., December 15, 2000; 275(51): 40628 - 40634. [Abstract] [Full Text] [PDF]

				M. P. Gustafson, C. F. Thomas Jr., F. Rusnak, A. H. Limper, and E. B. Leof Differential Regulation of Growth and Checkpoint Control Mediated by a Cdc25 Mitotic Phosphatase from Pneumocystis carinii J. Biol. Chem., January 5, 2001; 276(1): 835 - 843. [Abstract] [Full Text] [PDF]