Rat par4 (prostate apoptosis response) gene was isolated as the result of a screen
for genes transcriptionally induced by apoptotic signals in the rat ventral prostate. Johnstone et al. (1996) identified a
protein, designated human par-4 by them, which interacted with WT1 , the Wilms tumor suppressor protein.
Human PAR4 gene encodes a 342-amino acid polypeptide containing
a putative nuclear localization signal and a putative leucine zipper domain. Northern blotting showed that PAR4 is
expressed ubiquitously.
NCBI Summary:
The tumor suppressor WT1 represses and activates transcription. Apoptosis response protein is a WT1-interacting protein that itself functions as a transcriptional repressor. It contains a putative leucine zipper domain which interacts with the zinc finger DNA binding domain of WT1. Apoptosis response protein is specifically upregulated during apoptosis of prostate cells.
General function
Apoptosis, Nucleic acid binding, DNA binding, Transcription factor
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Cellular localization
Nuclear
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Ovarian function
Follicle atresia
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Boghaert ER, et al 1997 reported the immunohistochemical analysis of the proapoptotic protein Par-4 in normal rat tissues.
Par-4 protein is constitutively expressed in various cell lines and is functionally required but not sufficient for apoptosis. Induction of Par-4 in cultured cells is found exclusively during apoptosis, and ectopic overexpression of Par-4 enhances the potency of apoptotic stimuli. Western or Northern blot analysis on mRNA or protein extracts, respectively, from rat organs revealed that the expression of Par-4 was ubiquitous and was not restricted to any specific organ(s). To further identify specific cell types that expressed Par-4, we performed an immunohistochemical analysis of the protein in paraffin-embedded sections of various organs from rats. Our findings indicated that consistent with its proapoptotic role, Par-4 is expressed in apoptotic granulosa cells of atretic ovarian follicles and in terminally differentiated cells, such as the cardiomyocytes, cerebellar Purkinje cells, and pyramidal cells of the hypothalamus.
Taken together, the widespread expression of Par-4 in various adult cell types underscores the physiological importance of the protein. The observation of constitutive Par-4 expression in the stem cell compartments is inconsistent with the probability of apoptosis per se and can be extended to determine whether Par-4 plays a role in other cellular processes.
Expression regulated by
FSH
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Ovarian localization
Granulosa
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Regulation of the expression of prostate apoptosis response protein 4 (Par-4) in rat granulosa cells. Gonzalez IH et al. The par-4 gene, directs the expression of a protein in the rat ventral prostate after apoptotic stimuli but not growth stimulatory, growth arresting or necrotic signals. Since Par-4 expression appears to be ubiquitous we investigated the possibility of Par-4 having a role in the rat ovary granulosa cells apoptotic death. Par-4 mRNA was detected by RT-PCR with oligonucleotides designed to prime Par-4 leucine zipper in the ovaries of 12 day old rats and reached the higher levels in 24 days old rats. In situ hybridization analysis revealed that Par-4 expression is restricted to granulosa cells. PMSG priming of 24 day old rats for 2 days greatly reduced Par-4 expression in granulosa cells as determined by in situ hybridization, RT-PCR of mRNA and protein immunodetection with Western blot. Granulosa cells placed in serum-fee culture, exhibited increased levels of Par-4 mRNA and protein, in good correlation with the degree of apoptosis. The culture-induced increases in Par-4 are significantly prevented by FSH. Transient transfection of granulosa cells with Par-4 leucine zipper domain that functions as a dominant-negative regulator of Par-4 activity resulted in lower rates of apoptosis while overexpression of the full length Par-4 counteracted FSH effects on apoptosis. Par-4 association with PKCzeta which is supposed to inhibit this kinase mediated antiapoptotic way is also prevented by FSH and, FSH antiapoptotic effects are counteracted by a PKCzeta specific inhibitor. These findings indicate that FSH by suppressing Par-4 expression in the ovary activates PKCzeta-dependent antiapoptotic pathway and suggest that Par-4 is part of the mechanism underlying granulosa cells apoptotic demise.