APRIN is a unique Pds5 paralog with features of a chromatin regulator in hormonal differentiation

Abstract

Activation of steroid receptors results in global changes of gene expression patterns. Recent studies showed that steroid receptors control only a portion of their target genes directly, by promoter binding. The majority of the changes are indirect, through chromatin rearrangements. The mediators that relay the hormonal signals to large-scale chromatin changes are, however, unknown. We report here that APRIN, a novel hormone-induced nuclear phosphoprotein has the characteristics of a chromatin regulator and may link endocrine pathways to chromatin. We showed earlier that APRIN is involved in the hormonal regulation of proliferative arrest in cancer cells. To investigate its function we cloned and characterized APRIN orthologs and performed homology and expression studies. APRIN is a paralog of the cohesin-associated Pds5 gene lineage and arose by gene-duplication in early vertebrates. The conservation and domain differences we found suggest, however, that APRIN acquired novel chromatin-related functions (e.g. the HMGlike domains in APRIN, the hallmarks of chromatin regulators, are absent in Pds5). We show that in interphase nuclei APRIN localizes in the euchromatin/heterochromatin interface and we also identified its DNA-binding and nuclear import signal domains. Our results indicate that APRIN, in addition to its Pds5 similarity, has the features and localization of a hormone-induced chromatin regulator.

The cohesin-interacting protein, precocious dissociation of sisters 5A/sister chromatid cohesion protein 112, is up-regulated in human astrocytic tumors

“…The human Pds5B protein, a paralog of Pds5A, originally isolated as androgene shutoff gene 3 (AS3) from LNCaP prostate cancer cell lines (61) and later designated as APRIN, is a chromatin regulator in hormonal differentiation (62). It shares 73% amino acid identity with Pds5A (Table I) and has been shown to be involved in the regulation of proliferative arrest in cancer cells in response to hormones (61,62).…”

“…It shares 73% amino acid identity with Pds5A (Table I) and has been shown to be involved in the regulation of proliferative arrest in cancer cells in response to hormones (61,62). It is a putative tumor suppressor (63,64).…”

Gene Regulation by Cohesin in Cancer: Is the Ring an Unexpected Party to Proliferation?

“…Cohesin's role in the response to ecdysone involves regulating transcription of the EcR gene (74)(75)(76) and directly regulating ecdysone-responsive gene transcription (76,77). Remarkably, in humans, cohesin also appears to play an important role in the transcriptional response to androgen and estrogen (88,(114)(115)(116).…”

Loss of a cohesin-linked suppressor APRIN (Pds5b) disrupts stem cell programs in embryonal carcinoma: an emerging cohesin role in tumor suppression

“…APRIN evolved by gene duplication from the ancient Pds5 lineage, which shows high conservation from yeast to human (Geck et al, 1999;Maffini et al, 2008). Pds5A, the vertebrate ortholog of this lineage (SCC112 in human) (Kumar et al, 2004;Zheng et al, 2008), is a cohesin-associated protein with long evolution from unicellular eukaryotes (Berney and Pawlowski, 2006).…”

“…Release 12 of the Pfam-A database (2004) identified that APRIN is a chimeric gene with two successive acquisitions of unique HMG DNA-binding domains (AT-hooks), not present in Pds5A or any of the cohesin factors. Furthermore, APRIN diversified extensively, by 27% from its human Pds5A paralog (Maffini et al, 2008).…”