Dopamine receptor subtypes D₁ and D₂, and many other seven-transmembrane receptors including adenosine receptor A_2A, are colocalized in striatum of brain. These receptors stimulate or inhibit adenylyl cyclases (ACs) to produce distinct physiological and pharmacological responses and interact with each other synergistically or antagonistically at various levels. The identity of the AC isoform that is coupled to each of these receptors, however, remains unknown. To investigate the in vivo role of the type 5 adenylyl cyclase (AC5), which is preferentially expressed in striatum, mice deficient for the AC5 gene were generated. The genetic ablation of the AC5 gene eliminated >80% of forskolin-induced AC activity and 85–90% of AC activity stimulated by either D₁ or A_2A receptor agonists in striatum. However, D₁- or A_2A-specific pharmaco-behaviors were basically preserved, whereas the signal cascade from D₂ to AC was completely abolished inAC5^−/−, and motor activity of AC5^−/− was not suppressed by treatment of cataleptic doses of the antipsychotic drugs haloperidol and sulpiride. Interestingly, both haloperidol and clozapine at low doses remarkably increased the locomotion ofAC5^−/− in the open field test that was produced in part by a common mechanism that involved the increased activation of D₁ dopamine receptors. Together, these results suggest that AC5 is the principal AC integrating signals from multiple receptors including D₁, D₂, and A_2A in striatum and the cascade involving AC5 among diverse D₂ signaling pathways is essential for neuroleptic effects of antipsychotic drugs.

Leucine zipper/EF hand–containing transmembrane-1 (LETM1) is a mitochondrial inner membrane protein that was first identified in Wolf-Hirschhorn syndrome, and was deleted in nearly all patients with the syndrome. LETM1 encodes for the human homologue of yeast Mdm38p, which is a mitochondria-shaping protein of unclear function. Here, we describe LETM1-mediated regulation of mitochondrial ATP production and biogenesis. We show that LETM1 overexpression can induce necrotic cell death in HeLa cells, in which LETM1 reduces mitochondrial biogenesis and ATP production. LETM1 acts as an anchor protein and associates with mitochondrial ribosome protein L36. Adenovirus-mediated overexpression of LETM1 reduced mitochondrial mass and expression of many mitochondrial proteins. LETM1-mediated inhibition of mitochondrial biogenesis enhanced glycolytic ATP supply and activated protein kinase B activity and cell survival signaling. The expression levels of LETM1 were significantly increased in multiple human cancer tissues compared with normals. These data suggest that LETM1 serves as an anchor protein for complex formation with the mitochondrial ribosome and regulates mitochondrial biogenesis. The increased expression of LETM1 in human cancer suggests that dysregulation of LETM1 is a key feature of tumorigenesis. [Cancer Res 2009;69(8):3397–404]

The most common therapy for estrogen receptor–positive breast cancer is antihormone therapy, such as tamoxifen. However, acquisition of resistance to tamoxifen in one third of patients presents a serious clinical problem. Polo-like kinase 1 (Plk1) is a key oncogenic regulator of completion of G2–M phase of the cell cycle. We assessed Plk1 expression in five chemoresistant cancer cell types and found that Plk1 and its downstream phosphatase Cdc25c were selectively overexpressed in tamoxifen-resistant MCF-7 (TAMR-MCF-7) breast cancer cells. Real-time monitoring of cell proliferation also showed that TAMR-MCF-7 cells were more sensitive to inhibition of cell proliferation by the ATP-competitive Plk1 inhibitor BI2536 than were the parent MCF-7 cells. Moreover, BI2536 suppressed expression of epithelial–mesenchymal transition marker proteins and 3D spheroid formation in TAMR-MCF-7 cells. Using TAMR-MCF-7 cell–implanted xenograft and spleen–liver metastasis models, we showed that BI2536 inhibited tumor growth and metastasis in vivo. Our results suggest that Plk1 could be a novel target for the treatment of tamoxifen-resistant breast cancer. Mol Cancer Ther; 17(4); 825–37. ©2018 AACR.