Role of Acinus in regulating retinoic acid-responsive gene pre-mRNA splicing.

Acinus-S' is a corepressor for retinoic acid receptor (RAR)-dependent gene transcription and has been suggested to be involved in RNA processing. In this study, the role of Acinus isoforms in regulating pre-mRNA splicing was explored using in vivo splicing assays. Both Acinus-L and Acinus-S', with the activity of Acinus-L higher than that of Acinus-S', increase the splicing of a retinoic acid (RA)-responsive minigene containing a weak 5' splice site but not a RA-responsive minigene containing a strong 5' splice site.

The SAP motif and C-terminal RS- and RD/E-rich region influences the sub-nuclear localization of Acinus isoforms.

Acinus has been reported to function in apoptosis, RNA processing and regulation of gene transcription including RA-dependent transcription. There are three different isoforms of Acinus termed Acinus-L, Acinus-S', and Acinus-S. The isoforms of Acinus differ in their N-terminus while the C-terminus is consistent in all isoforms.

Role of COUP-TFI during retinoic acid-induced differentiation of P19 cells to endodermal cells.

Retinoic acid (RA) is a positive regulator of P19 cell differentiation. Silencing of pre-B cell leukemia transcription factors (PBXs) expression in P19 cells (AS cells) results in a failure of these cells to differentiate to endodermal cells upon RA treatment. Chicken Ovalbumin Upstream Promoter Transcription Factor I (COUP-TFI) is an orphan member of the steroid-thyroid hormone superfamily.

Role of SF-1 and DAX-1 during differentiation of P19 cells by retinoic acid.

Retinoic acid (RA) is critical for embryonic development and cellular differentiation. Previous work in our laboratory has shown that blocking the RA-dependent increase in pre-β cell leukemia transcription factors (PBX) mRNA and protein levels in P19 cells prevents endodermal and neuronal differentiation. Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1) and steroidogenic factor (SF-1) were found by microarray analysis to be regulated by PBX in P19 cells.

PP2A interaction with Rb2/p130 mediates translocation of Rb2/p130 into the nucleus in all-trans retinoic acid-treated ovarian carcinoma cells.

One of the mechanisms by which all-trans retinoic acid (ATRA) has been shown to suppress the growth of CAOV3 ovarian carcinoma cells involves an increase in the accumulation of Rb2/p130 protein, a member of the retinoblastoma family of tumor suppressors. This increase in accumulation of RB2/p130 by ATRA results from increased stability of Rb2/p130 protein as a result of an increase in dephosphorylation of the protein by the serine/threonine phosphatase PP2A. We show that upon ATRA treatment, PP2A interacts with the Rb2/p130 C-terminus and specifically dephosphorylates two residues (S1080 and T1097) adjacent to NLS1 and NLS2 of Rb2/p130.

Expression of homeobox genes in oral squamous cell carcinoma cell lines treated with all-trans retinoic acid.

Oral squamous cell carcinoma (OSCC) may arise from potentially malignant oral lesions. All-trans retinoic acid (atRA), which plays a role in cell growth and differentiation, has been studied as a possible chemotherapeutic agent in the prevention of this progression. While the mechanism by which atRA suppresses cell growth has not been completely elucidated, it is known that homeobox genes are atRA targets.

HACE1: A novel repressor of RAR transcriptional activity.

The diverse biological actions of retinoic acid (RA) are mediated by RA receptors (RARs) and retinoid X receptors (RXRs). While the coregulatory proteins that interact with the ligand-dependent AF-2 in the E region are well studied, the ligand-independent N-terminal AF-1 domain-interacting partners and their influence(s) on the function of RARs are poorly understood. HECT domain and Ankyrin repeat containing E3 ubiquitin-protein ligase (HACE1) was isolated as a RARbeta(3) AB region interacting protein.

S10 phosphorylation of p27 mediates atRA induced growth arrest in ovarian carcinoma cell lines.

All trans retinoic acid (atRA) has been shown to inhibit the growth of CAOV3 ovarian carcinoma cells and to elevate the level of p27 cyclin-dependent kinase inhibitor. We report here that phosphorylation at S10 residue is an important event in mediating p27 role in atRA induced growth arrest. atRA treatment of atRA sensitive CAOV3 cells increases the levels of S10 phospho-p27 in both nuclear and cytoplasmic cell compartments.

Characterization of alterations of Rb2/p130 tumor suppressor in all-trans-retinoic acid resistant SK-OV3 ovarian carcinoma cells.

Rb2/p130 tumor suppressor protein regulates cell cycle progression primarily through interactions with members of the E2F family of transcription factors and repression of the transactivation of E2F target genes. In ATRA sensitive ovarian carcinoma CA-OV3 cells, a dramatic increase in Rb2/p130 protein mediates growth arrest at G0/G1. However, although Rb2/p130 is expressed at high levels in SK-OV3 cells, they fail to growth arrest in response to ATRA treatment.

Acinus-S' represses retinoic acid receptor (RAR)-regulated gene expression through interaction with the B domains of RARs.

The diverse biological actions of retinoic acid (RA) are mediated by RA receptors (RARs) and retinoid X receptors (RXRs). Modulation of transcription by RARs/RXRs is achieved through two activation functions, ligand-independent AF-1 and ligand-dependent AF-2, located in the A/B and E domains, respectively. While the coregulatory proteins that interact with the E domain are well studied, the A/B domain-interacting partners and their influence(s) on the function of RARs are poorly understood.

Insulin receptor substrate-1 is an important mediator of ovarian cancer cell growth suppression by all-trans retinoic acid.

There is a need to identify more effective drugs for the treatment of ovarian cancer as it is the leading cause of death among gynecologic tumors. All-trans retinoic acid (ATRA), a natural retinoid, arrests the growth of CA-OV3 ovarian carcinoma cells in G(0)-G(1). Because the insulin-like growth factor-I receptor has been implicated in the proliferation of various tumors, we investigated its potential role in the suppression of ovarian cancer cell growth by ATRA.

Retinoids in biological control and cancer.

More than 80 years ago, Wolbach and Howe provided the first evidence suggesting a link between alterations within human cells that lead to malignancies and vitamin A deficiencies (Wolbach and Howe 1925 Nutr. Rev. 36: 16-19).

GADD45A is a mediator of CD437 induced apoptosis in ovarian carcinoma cells.

Ovarian cancer is one of the leading causes of cancer death in women. A number of studies have suggested that synthetic retinoids may play an important role as an ovarian cancer chemotherapeutic agent. The synthetic retinoid CD 437 induces apoptosis in ovarian tumor cells by a mechanism that is not completely understood.

Role of retinoic acid in the differentiation of embryonal carcinoma and embryonic stem cells.

Retinoic acid (RA), the most potent natural form of vitamin A, plays an important role in many diverse biological processes such as embryogenesis and cellular differentiation. This chapter is a review of the mechanism of action of RA and the role of specific RA-regulated genes during the cellular differentiation of embryonal carcinoma (EC) and embryonic stem (ES) cells. RA acts by binding to its nuclear receptors and inducing transcription of specific target genes.

Retinoid targets for the treatment of cancer.

Retinoic acid (RA), the most potent natural retinoid, is essential for normal cell growth and differentiation. The RA signaling pathway is multistep, involving the precise regulation of retinoid levels and the control of RA-dependent gene expression in target cells. Within this complex scheme, there are many different aberrations in the RA signaling pathway of tumor cells that have been found to be associated with abnormal cell growth and tumorigenesis.

Epigallocatechin-3-gallate delivers hydrogen peroxide to induce death of ovarian cancer cells and enhances their cisplatin susceptibility.

The green tea polyphenol epigallocatechin-3-gallate (EGCG) has cancer chemopreventive properties against various types of cancers. The compound is known to attack various targets in transformed cells. In this report, we examined the action of EGCG on ovarian cancer cells.

Interaction of PP2A catalytic subunit with Rb2/p130 is required for all-trans retinoic acid suppression of ovarian carcinoma cell growth.

All-trans retinoic acid (ATRA) treatment causes CAOV3 ovarian carcinoma cells to growth arrest in the G0/G1 phase and to elevate the level of Rb2/p130 protein. PP2A, a serine/threonine phosphatase, binds and dephosphorylates Rb2/p130, thereby increasing the half-life of Rb2/p130 in the cell. In order to further characterize the interaction between Rb2/p130 and PP2A upon ATRA treatment, we examined the posttranslational modification of PP2A.

Retinoic acid induced repression of AP-1 activity is mediated by protein phosphatase 2A in ovarian carcinoma cells.

In previous studies we have shown that all-trans retinoic acid (atRA)-treatment of the atRA-sensitive ovarian carcinoma cell line CA-OV3 repressed AP-1 activity by about 50%, while a similar effect was not observed in the atRA-resistant ovarian carcinoma cell line, SK-OV3. These results suggested that the repression of AP-1 activity may be one of the mechanisms by which atRA inhibits the growth of atRA-sensitive CA-OV3 cells. In the present studies, we investigated further the molecular mechanism by which AP-1 activity is repressed by atRA.

Retinoic acid receptors and cancers.

Studies utilizing experimental animals, epidemiological approaches, cellular models, and clinical trials all provide evidence that retinoic acid and some of its synthetic derivatives (retinoids) are useful pharmacological agents in cancer therapy and prevention. In this chapter, we first review the current knowledge of retinoic acid receptors (RARs) and their role in mediating the actions of retinoic acid. We then focus on a discussion of RARalpha and acute promyelocytic leukemia followed by a discussion of the role of RARs, in particular RARbeta expression, in other cancer types.

Frequent loss of pRb2/p130 in human ovarian carcinoma.

Purpose: RB2/p130, a member of the retinoblastoma gene family, maps to human chromosome 16q12.2, a region in which deletions have been found in several human neoplasms including breast, prostatic, and ovarian carcinoma. We sought to evaluate pRb2/p130 protein expression and function in ovarian carcinoma.

Retinoic acid regulates the expression of PBX1, PBX2, and PBX3 in P19 cells both transcriptionally and post-translationally.

Pre-B cell leukemia transcription factors (PBXs) are important co-factors for the transcriptional regulation mediated by a number of Hox proteins during embryonic development. It was previously shown that the expression of several Pbx genes is elevated in mouse embryo limb buds and embryonal carcinoma P19 cells upon retinoic acid (RA) treatment although the mechanism of this induction is not well understood. In this report, we demonstrate that PBX1a, PBX1b, PBX2, and PBX3 mRNAs and PBX1/2/3 proteins are induced during endodermal and neuronal differentiation of P19 cells in a RAR-dependent subtype-unspecific manner following RA treatment.

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines.

Apoptosis is also known as programmed cell death. Apoptosis plays an essential role in maintaining normal tissue and cell physiology in multicellular organisms. Clearance of aberrant or pre-cancerous cells occurs through the induction of apoptosis.

p27/Kip1 mediates retinoic acid-induced suppression of ovarian carcinoma cell growth.

We have investigated the mechanisms by which all-trans retinoic acid (ATRA) causes growth inhibition of ovarian carcinoma cells. As a model, we have studied the CAOV3 cell line, which is sensitive to ATRA, and the SKOV3 cell line, which is resistant. We have found that treatment of CAOV3 cells with ATRA causes a 5-10 fold increase in the protein level of the cyclin dependent kinase inhibitor p27/Kip1.

Pre-B cell leukemia transcription factor (PBX) proteins are important mediators for retinoic acid-dependent endodermal and neuronal differentiation of mouse embryonal carcinoma P19 cells.

Pre-B cell leukemia transcription factors (PBXs) act as cofactors in the transcriptional regulation mediated by Homeobox proteins during embryonic development and cellular differentition. PBX1 protein is expressed throughout murine embryonic development, and its deletion in mice disrupts chondrogenesis. PBX protein levels are also increased in mouse embryonal carcinoma P19 cells during retinoic acid (RA)-induced differentiation.