Activation of the cyclin D1 Gene by the E1A-associated Protein p300 through AP-1 Inhibits Cellular Apoptosis

Abstract

The adenovirus E1A protein interferes with regulators of apoptosis and growth by physically interacting with cell cycle regulatory proteins including the retinoblastoma tumor suppressor protein and the coactivator proteins p300/CBP (where CBP is the CREB-binding protein). The p300/CBP proteins occupy a pivotal role in regulating mitogenic signaling and apoptosis. The mechanisms by which cell cycle control genes are directly regulated by p300 remain to be determined. The cyclin D1 gene, which is overexpressed in many different tumor types, encodes a regulatory subunit of a holoenzyme that phosphorylates and inactivates PRB. In the present study E1A12S inhibited the cyclin D1 promoter via the amino-terminal p300/CBP binding domain in human choriocarcinoma JEG-3 cells. p300 induced cyclin D1 protein abundance, and p300, but not CBP, induced the cyclin D1 promoter. cyclin D1 or p300 overexpression inhibited apoptosis in JEG-3 cells. The CH3 region of p300, which was required for induction of cyclin D1, was also required for the inhibition of apoptosis. p300 activated the cyclin D1 promoter through an activator protein-1 (AP-1) site at ؊954 and was identified within a DNA-bound complex with c-Jun at the AP-1 site. Apoptosis rates of embryonic fibroblasts derived from mice homozygously deleted of the cyclin D1 gene (cyclin D1 ؊/؊ ) were increased compared with wild type control on several distinct matrices. p300 inhibited apoptosis in cyclin D1 ؉/؉ fibroblasts but increased apoptosis in cyclin D1؊/؊ cells. The anti-apoptotic function of cyclin D1, demonstrated by sub-G 1 analysis and annexin V staining, may contribute to its cellular transforming and cooperative oncogenic properties.

Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1

“…Mitigating this are the data in this report along with other investigations utilizing direct gain-and-loss of D cyclin function in lymphoid cells (Rhee et al, 1995;Warenius et al, 1996), cells from pancreatic carcinoma (Kornmann et al, 1997) and lung cancer cells (Driscoll et al, 1999). Moreover, recent ®ndings demonstrate that transcriptional upregulation of endogenous cyclin D1 by activating its promoter, inhibits apoptosis (Albanese et al, 1999), whereas antisense cyclin D1 induces apoptosis and decreases tumor size in human squamous carcinomas (Sauter et al, 1999). These studies show that many types of cells driven to ectopically transit the cell cycle by growth promoters other than D-type cyclins can be rescued by D cyclins from serum deprivation, lethal irradiation or cytostatic drugs.…”

“…Of particular note are data which show that c-Myc and cyclin D3 individually sensitize lymphoid cells to dexamethasone-induced apoptosis, whereas co-expression of c-Myc and cyclin D3 rescues cells (Rhee et al, 1995); results in close accord with our ®ndings. In concert with these in vitro experiments, developmental studies in cyclin D1 null mice suggest a critical role for cyclin D1 in preserving viability of retinal photoreceptor cells , and in suppression of apoptosis in cyclin D1 knockout ®broblasts (Albanese et al, 1999).…”

Physical and functional cooperation between AP-1 and β-catenin for the regulation of TCF-dependent genes

“…These observations therefore clearly indicate that AP-1 proteins associate in vivo with b-catenin for transactivating the cyclin D1 promoter after serum stimulation. The AP-1 proteins c-Jun, JunD and c-Fos have already been implicated as transcriptional activators of the cyclin D1 promoter through their binding to the TRE and/or the CRE elements (Brown et al, 1998;Albanese et al, 1999;Kane et al, 1999;Bakiri et al, 2000), whereas the role of JunB is more debated (Albanese et al, 1995;Mechta et al, 1997;Bakiri et al, 2000). Our present data strongly suggest that JunB may potentially play a positive role on cyclin D1 when cooperating with b-catenin.…”

The RNA-binding protein La contributes to cell proliferation and CCND1 expression

“…To support a functional link between La expression, CCND1 expression and cell proliferation, we compared the proliferation rate of La-depleted and control-treated immortalized mouse embryonic fibroblast (MEF) cells originating from CCND1 knockout mice (MEF CCND1À/À 3T3 cells (Albanese et al, 1999;Wang et al, 2003)). In contrast to all other tested cell lines, the proliferation rate of La-depleted MEF CCND1À/À was not reduced (Figure 5a).…”

“…New HeLa cell cultures were established every 2-3 months. MEF CCND1À/À 3T3 cells (Albanese et al, 1999;Wang et al, 2003) were kindly provided by RG Pestell (Thomas Jefferson University, Philadelphia, PA, USA). All cells were cultured in complete DMEM plus 10% fetal bovine serum.…”