AKAP95 promotes cell cycle progression via interactions with cyclin E and low molecular weight cyclin E.

AKAP95 in lung cancer tissues showed higher expression than in paracancerous tissues. AKAP95 can bind with cyclin D and cyclin E during G1/S cell cycle transition, but its molecular mechanisms remain unclear. To identify the mechanism of AKAP95 in cell cycle progression, we performed AKAP95 transfection and silencing in A549 cells, examined AKAP95, cyclin E1 and cyclin E2 expression, and the interactions of AKAP95 with cyclins E1 and E2. Results showed that over-expression of AKAP95 promoted cell growth and AKAP95 bound cyclin E1 and E2, low molecular weight cyclin E1 (LWM-E1) and LWM-E2. Additionally AKAP95 bound cyclin E1 and LMW-E2 in the nucleus during G1/S transition, bound LMW-E1 during G1, S and G2/M, and bound cyclin E2 mainly on the nuclear membrane during interphase. Cyclin E2 and LMW-E2 were also detected. AKAP95 over-expression increased cyclin E1 and LMW-E2 expression but decreased cyclin E2 levels. Unlike cyclin E1 and LMW-E2 that were nuclear located during the G1, S and G1/S phases, cyclin E2 and LMW-E1 were expressed in all cell cycle phases, with cyclin E2 present in the cytoplasm and nuclear membrane, with traces in the nucleus. LMW-E1 was present in both the cytoplasm and nucleus. The 20 kDa form of LMW-E1 showed only cytoplasmic expression, while the 40 kDa form was nuclear expressed. The expression of AKAP95, cyclin E1, LMW-E1 and -E2, might be regulated by cAMP. We conclude that AKAP95 might promote cell cycle progression by interacting with cyclin E1 and LMW-E2. LMW-E2, but not cyclin E2, might be involved in G1/S transition. The binding of AKAP95 and LMW-E1 was found throughout cell cycle.

LPA signaling is required for dopaminergic neuron development and is reduced through low expression of the LPA1 receptor in a 6-OHDA lesion model of Parkinson's disease.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that activates at least five known G-protein-coupled receptors (GPCRs): LPA1-LPA5. The nervous system is a major locus for LPA1 expression. LPA has been shown to regulate neuronal proliferation, migration, and differentiation during central nervous system development as well as neuronal survival. Furthermore, deficient LPA signaling has been implicated in several neurological disorders including neuropathic pain and schizophrenia. Parkinson's disease (PD) is a neurodegenerative movement disorder that results from the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). The specific molecular pathways that lead to DA neuron degeneration, however, are poorly understood. The influence of LPA in the differentiation of mesenchymal stem cells (MSCs) into DA neurons in vitro and LPA1 expression in a 6-hydroxydopamine (6-OHDA) lesion model of PD in vivo were examined in the present study. LPA induced neuronal differentiation in 80.2 % of the MSC population. These MSCs developed characteristic neuronal morphology and expressed the neuronal marker, neuron-specific enolase (NSE), while expression of the glial marker, glial fibrillary acidic protein (GFAP), was absent. Moreover, 27.6 % of differentiated MSCs were positive for tyrosine hydroxylase (TH), a marker for DA neurons. In the 6-OHDA PD rat model, LPA1 expression in the substantia nigra was significantly reduced compared to control. These results suggest LPA signaling via activation of LPA1 may be necessary for DA neuron development and survival. Furthermore, reduced LPA/LPA1 signaling may be involved in DA neuron degeneration thus contributing to the pathogenesis of PD.

[Relationship between AKAP95, cyclin E1, cyclin D1, and clinicopathological parameters in lung cancer tissue].

OBJECTIVE: To investigate the correlation between expression of A-kinase anchoring protein 95 (AKAP95) and protein expression of cyclin E1 and cyclin D1 in lung cancer tissue. METHODS: Fifty-one cases of lung cancer were included in the study. The protein expression of AKAP95, cyclin E1, and cyclin D1 were measured by immunohistochemistry. RESULTS: The protein expression of cyclin E1 in lung cancer tissues was significantly higher than that in para-cancerous tissues (positive rate: 75.56%vs 20%, P < 0.01); its expression showed no relationship with histopathological type, lymph node metastasis, and cellular differentiation (P > 0.05). The protein expression of cyclin D1 in lung cancer tissues was higher than that in para-cancerous tissues (positive rate: 69.39% vs 14.29%); its expression showed a significant relationship with histopathological type (P < 0.05). The expression of AKAP95 was correlated with the protein expression of cyclin E1 and cyclin D1 in lung cancer tissues (P < 0.01). CONCLUSION: Cyclin E1 and cyclin D1 are highly expressed in lung cancer tissue, suggesting that they play an important role in the development and progression of lung cancer. The protein expression of cyclin E1 has no relationship with cellular differentiation, lymph node metastasis, and histopathological type of lung cancer, and the protein expression of cyclin D1 has a significant relationship with histopathological type. The expression of AKAP95 is correlated with the protein expression of cyclin E1 and cyclin D1 in lung cancer tissue.