PR55α-containing protein phosphatase 2A complexes promote cancer cell migration and invasion through regulation of AP-1 transcriptional activity.

The proto-oncogene c-Jun is a component of activator protein-1 (AP-1) transcription factor complexes that regulates processes essential for embryonic development, tissue homeostasis and malignant transformation. Induction of gene expression by c-Jun involves stimulation of its transactivation ability and upregulation of DNA binding capacity. While it is well established that the former requires JNK-mediated phosphorylation of S63/S73, the mechanism(s) through which binding of c-Jun to its endogenous target genes is regulated remains poorly characterized. Here we show that interaction of c-Jun with chromatin is positively regulated by protein phosphatase 2A (PP2A) complexes targeted to c-Jun by the PR55α regulatory subunit. PR55α-PP2A specifically dephosphorylates T239 of c-Jun, promoting its binding to genes regulating tumour cell migration and invasion. PR55α-PP2A also enhanced transcription of these genes, without affecting phosphorylation of c-Jun on S63. These findings suggest a critical role for interplay between JNK and PP2A pathways determining the functional activity of c-Jun/AP-1 in tumour cells.

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells.

Fos-related antigen-1 (Fra-1) is a member of the Activator Protein-1 (AP-1) transcription factor superfamily that is overexpressed in a variety of cancers, including colon, breast, lung, bladder and brain. High Fra-1 levels are associated with enhanced cell proliferation, survival, migration and invasion. Despite its frequent overexpression, the molecular mechanisms that regulate the accumulation of Fra-1 proteins in tumour cells are not well understood. Here, we show that turnover of Fra-1, which does not require ubiquitylation, is cooperatively regulated by two distinct mechanisms-association with the 19S proteasomal subunit, TBP-1, and by a C-terminal degron, which acts independently of TBP-1, but is regulated by RAS-ERK (extracellular signal-regulated kinase) signalling. TBP-1 depletion stabilized Fra-1 and further increased its levels in tumour cells expressing RAS-ERK pathway oncogenes. These effects correlated with increased AP-1 transcriptional activity. We suggest that during Fra-1 degradation, association with TBP-1 provides a mechanism for ubiquitin-independent proteasomal recognition, while the C terminus of the protein regulates its subsequent proteolytic processing.

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL.

Fos-related antigen 1 (Fra-1) is a Fos family member overexpressed in several types of human cancers. Here, we report that Fra-1 is highly expressed in the muscle-invasive form of the carcinoma of the bladder (80%) and to a lesser extent in superficial bladder cancer (42%). We demonstrate that in this type of cancer Fra-1 is regulated via a C-terminal instability signal and C-terminal phosphorylation. We show that manipulation of Fra-1 expression levels in bladder cancer cell lines affects cell morphology, motility and proliferation. The gene coding for AXL tyrosine kinase is directly upregulated by Fra-1 in bladder cancer and in other cell lines. Importantly, our data demonstrate that AXL mediates the effect of Fra-1 on tumour cell motility but not on cell proliferation. We suggest that AXL may represent an attractive therapeutic target in cancers expressing high Fra-1 levels.

PP032. Unique features of long-term cardiovascular phenotype in young women with early-onset pre-eclampsia.

INTRODUCTION: Early-onset preeclampsia is associated with a greater risk of cardiovascular disease than late-onset preeclampsia. OBJECTIVES: We tested the hypothesis that young women, with previous early-onset preeclampsia, have unique differences in long term cardiovascular phenotype compared to late-onset preeclampsia or normal pregnancy. METHODS: 140 women (mean age 40 yrs) were followed up 6-13years following pregnancy. 90 had had preeclampsia (45 early onset (before 34 weeks of gestation), 45 late onset) and 50 had normotensive uncomplicated pregnancies. Women with cardiovascular risk factors present before pregnancy were excluded. Fasting lipids, glucose, insulin and circulating cytokines were measured. Central blood pressure (BP) and arterial stiffness (pulse wave velocity (PWV)/augmentation index (AI)) were assessed by applanation tonometry, common carotid intima media thickness (cIMT) by ultrasound and cutaneous capillary density by intravital microscopy. 46 women returned for assessment of cardiac structure and function by magnetic resonance and echocardiography as well as ambulatory blood pressure monitoring. RESULTS: All women with a previous history of preeclampsia had 5-10mmHg higher peripheral and central BP (P<0.001) as well as elevated total: HDL cholesterol (P<0.003), insulin resistance (P<0.04) and circulating TNFα (P<0.007). They also had increased arterial stiffness (P<0.04) and cIMT (P<0.005). Cardiac size and systolic function were preserved but there was evidence of abnormal diastolic relaxation (E/E' -P<0.04). In contrast early-onset preeclampsia was associated with characteristic differences in peri-pregnancy blood pressure, long term ambulatory measures and microvascular function. CONCLUSION: Early onset preeclampsia is associated with unique features in long term cardiovascular phenotype. Pregnancy disease characteristics may identify women at greatest potential benefit from monitoring and primary prevention.

[The effect of atenolol on contractility and hemodynamics of the infarcted heart in comparison to propranolol and practolol (author's transl)]. / Wirkung von Atenolol auf Kontraktilität und Hämodynamik im Vergleich zu Propranolol und Practolol beim Infarktherzen

In animals without myocardial infarction the new beta-sympathicolytic agent atenolol (4-[2'-hydroxy-3'-iso-propylaminopropoxy]-phenyl acetamide, ICI 66 082) dose-dependently decreased heart rate, systolic aortic pressure and cardiac output. Coronary mean flow, coronary resistance, stroke volume, left ventricular enddiastolic pressure and total peripheral vascular resistance did not change significantly. Atenolol significantly reduced myocardial contractility, expressed by (dp/dtmax), Vpm, t-(dp/dtmax) and pre-ejection period. Furthermore, the comparative studies in animals with myocardial infarction and concomitant reduced cardial efficiency revealed, that atenolol has neither a positive intrinsic activity as has practolol nor a negative intrinsic activity as has propranolol. The dose-contractility relation of atenolol resembles that of practolol: in low dosages a strong decrease is achieved, in higher dosages no further reduction of the contractility parameters is observed. Because of the strong negative inotropic and blood pressure lowering effect it is suggested to use atenolol only with great caution in patients with reduced cardiac efficiency.