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J. Biol. Chem., Vol. 279, Issue 31, 32373-32384, July 30, 2004

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PINA Is Essential for Growth and Positively Influences NIMA Function in Aspergillus nidulans^*

James D. Joseph, Scott N. Daigle, and Anthony R. Means

From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710

The phospho-Ser/Thr-directed prolyl-isomerase Pin1 was originally identified in vertebrate systems as a negative regulator of NIMA, a Ser/Thr protein kinase that regulates the G₂/M transition in Aspergillus nidulans. Here we explore the physiological roles of the Pin1 orthologue, PINA, in A. nidulans and evaluate the relevance of the interaction of PINA with NIMA in this fungus. We find pinA to be an essential gene in A. nidulans. In addition, when PINA levels are reduced 50-fold the cells grow at a reduced rate. Upon germination under conditions that repress PINA expression, the cells are delayed in the interphase activation of NIMX^cdc2, whereas they traverse the other phases of the cell cycle at a similar rate to controls. These results indicate that a marked reduction of PINA results in a lengthening of G₁. Additionally, PINA repression increases the rate at which the cells enter mitosis following release from a hydroxyurea arrest without altering the sensitivity of the fungus to agents that activate the replication or DNA damage checkpoints. In contrast to predictions based on Pin1, the physical interaction between PINA and NIMA is primarily dependent upon the prolylisomerase domain of PINA and the C-terminal 303 amino acids of NIMA. Finally, reduction of PINA levels exacerbates the nimA5 temperature-sensitive mutant, whereas overexpression of PINA decreases the severity of this mutation, results that are consistent with a positive genetic interaction between PINA and NIMA. Thus, although PINA is essential and positively regulates NIMA function, A. nidulans is most sensitive to a reduction in PINA concentration in G₁ rather than in G₂/M.

Received for publication, May 14, 2004

^* This work was supported by National Institutes of Health Training Grant 2T32DK07568-13 (to J. D. J.) and Research Grant CA82845 (to A. R. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Current address: Schering-Plough Corp., Kenilworth, NJ 07033.

To whom correspondence should be addressed: Dept. of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813, Durham, NC 27710. Tel.: 919-681-6209; Fax: 919-681-7767; E-mail: means001{at}mc.duke.edu.

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This article has been cited by other articles:

				E. S. Yeh, B. O. Lew, and A. R. Means The Loss of PIN1 Deregulates Cyclin E and Sensitizes Mouse Embryo Fibroblasts to Genomic Instability J. Biol. Chem., January 6, 2006; 281(1): 241 - 251. [Abstract] [Full Text] [PDF]

				P. Ren, A. Rossettini, V. Chaturvedi, and S. D. Hanes The Ess1 prolyl isomerase is dispensable for growth but required for virulence in Cryptococcus neoformans Microbiology, May 1, 2005; 151(5): 1593 - 1605. [Abstract] [Full Text] [PDF]

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