CDK5 phosphorylates eNOS at Ser‐113 and regulates NO production

Lee, Chien Hsing; Wei, Yin; Huang, Yi-Chung; Lin, Yuh Te; Lee, Yu Cheng; Lu, Pei Jung

doi:10.1002/jcb.22515

Cited by 9 publications

(7 citation statements)

References 33 publications

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“…Besides serine 1177, other point of phosphorylation may modulate eNOS activity, such as Thr495 and Ser113 22 23 . Thus, we detected the effect of tBHQ on these sites.…”

Section: Resultsmentioning

confidence: 99%

RETRACTED ARTICLE: Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway

Long

Luo

2016

Sci Rep

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Tert-butylhydroquinone (tBHQ), as an antioxidant, has been widely used for many years to prevent oxidization of food products. The aim of this study was to investigate whether tBHQ activates endothelial nitric oxide synthase (eNOS) to prevent endothelial dysfunction and lower blood pressure. The role of Akt in tBHQ-induced eNOS phosphorylation was examined in human umbilical vein endothelial cells (HUVEC) or in mice. tBHQ treatment of HUVEC increased both Akt-Ser473 phosphorylation, accompanied with increased eNOS-Ser1177 phosphorylation and NO release. Mechanically, pharmacologic or genetic inhibition of Akt abolished tBHQ-enhanced NO release and eNOS phosphorylation in HUVEC. Gain-function of PTEN or inhibition of 26S proteasome abolished tBHQ-enhanced Akt phosphorylation in HUVEC. Ex vivo analysis indicated that tBHQ improved Ach-induced endothelium-dependent relaxation in LPC-treated mice aortic arteries, which were abolished by inhibition of Akt or eNOS. In animal study, administration of tBHQ significantly increased eNOS-Ser1177 phosphorylation and acetylcholine-induced vasorelaxation, and lowered AngII-induced hypertension in wildtype mice, but not in mice deficient of Akt or eNOS. In conclusion, tBHQ via proteasome-dependent degradation of PTEN increases Akt phosphorylation, resulting in upregulation of eNOS-derived NO production and consequent improvement of endothelial function in vivo. In this way, tBHQ lowers blood pressure in hypertensive mice.

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“…Besides serine 1177, other point of phosphorylation may modulate eNOS activity, such as Thr495 and Ser113 22 23 . Thus, we detected the effect of tBHQ on these sites.…”

Section: Resultsmentioning

confidence: 99%

RETRACTED ARTICLE: Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway

Long

Luo

2016

Sci Rep

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“…3a ). The interaction between nestin and CDK5 modulates downstream molecules, including RAC1 and NOS3 [epithelial nitric oxide synthase (eNOS)] ( 23 – 25 ). Four of the 5 patients exhibited increased nestin expression and 3 of the 5 patients exhibited decreased CDK5 or RAC1 expression.…”

Section: Resultsmentioning

confidence: 99%

Nestin predicts a favorable prognosis in early ampullary adenocarcinoma and functions as a promoter of metastasis in advanced cancer

et al. 2014

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Nestin exhibits stemness characteristics and is over-expressed in several types of cancers. Downstream signaling of nestin [cyclin-dependent kinase 5 (CDK5) and Ras-related C3 botulinum toxin substrate 1 (Rac1)] functions in cancer to modulate cellular behaviors. We studied the function of nestin in ampullary adenocarcinoma. Immunohistochemistry (IHC), reverse transcription-polymerase chain reaction, and cDNA microarray of nestin in ampullary adenocarcinoma was compared with normal duodenum. CDK5 and Rac1 were assessed by western blotting. We hypothesized that nestin/CDK5/Rac1 signaling behaves different in early and advanced cancer. We found that the presence of nestin mRNA was increased in the early stages of cancer (T2N0 or T3N0) and advanced cancer with lymph node metastasis (T4N1). A total of 102 patients were enrolled in the IHC staining. Weak nestin expression was correlated with favorable characteristics of cancer, decreased incidence of local recurrence and lower risk of recurrence within 12 months after surgery. Patients with weak nestin expression had the most favorable recurrence-free survival rates. Patients with mild to strong nestin expression exhibited an advanced behavior of cancer and increased possibility of cancer recurrence. The reciprocal expression of nestin and RAC1 were explored using a cDNA microarray analysis in the early stages of ampullary adenocarcinoma. Increased level of CDK5 with simultaneously decreased expression of Rac1 was detected by western blotting of ampullary adenocarcinoma in patients without cancer recurrence. The activation of multiple oncogenic pathways, combined with the stemness characteristics of nestin, formed a complex network in advanced ampullary adenocarcinoma. Our study demonstrated that nestin performs a dual role in ampullary adenocarcinoma. Appropriate amount of nestin enhances CDK5 function to suppress Rac1 and excessive nestin/CDK5 participates in multiple oncogenic pathways to promote cancer invasiveness. Inhibiting nestin in patients who exhibit nestin-overexpressed ampullary adenocarcinoma may be a method of preventing cancer recurrence.

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“…In doing so, this work provides the first evidence for an in vivo role of Cdk5 in blood vessel formation. There have been various reports including ours, describing functions of Cdk5 in endothelial cells: in detail, endothelial Cdk5 was implicated in endothelial senescence [ 47 ], in neovascularization after ischemic stroke [ 48 ], and in diseases associated with NO dysfunction [ 49 , 50 ]. Our former studies demonstrated that small molecule Cdk5 inhibitors exert anti-angiogenic effects and that Cdk5 is implicated in endothelial cell migration by regulating the small GTPase Rac1 which was restricted to in vitro assays.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis

et al. 2016

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Therapeutic success of VEGF-based anti-angiogenic tumor therapy is limited due to resistance. Thus, new strategies for anti-angiogenic cancer therapy based on novel targets are urgently required. Our previous in vitro work suggested that small molecule Cdk5 inhibitors affect angiogenic processes such as endothelial migration and proliferation. Moreover, we recently uncovered a substantial role of Cdk5 in the development of lymphatic vessels. Here we pin down the in vivo impact of endothelial Cdk5 inhibition in angiogenesis and elucidate the underlying mechanism in order to judge the potential of Cdk5 as a novel anti-angiogenic and anti-cancer target. By the use of endothelial-specific Cdk5 knockout mouse models and various endothelial and tumor cell based assays including human tumor xenograft models, we show that endothelial-specific knockdown of Cdk5 results in excessive but non-productive angiogenesis during development but also in tumors, which subsequently leads to inhibition of tumor growth. As Cdk5 inhibition disrupted Notch function by reducing the generation of the active Notch intracellular domain (NICD) and Cdk5 modulates Notch-dependent endothelial cell proliferation and sprouting, we propose that the Dll4/Notch driven angiogenic signaling hub is an important and promising mechanistic target of Cdk5. In fact, Cdk5 inhibition can sensitize tumors to conventional anti-angiogenic treatment as shown in tumor xenograft models. In summary our data set the stage for Cdk5 as a drugable target to inhibit Notch-driven angiogenesis condensing the view that Cdk5 is a promising target for cancer therapy.

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CDK5 phosphorylates eNOS at Ser‐113 and regulates NO production

Cited by 9 publications

References 33 publications

RETRACTED ARTICLE: Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway

RETRACTED ARTICLE: Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway

Nestin predicts a favorable prognosis in early ampullary adenocarcinoma and functions as a promoter of metastasis in advanced cancer

Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis

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