Dataset Information

Deletion of Rap1b, but not Rap1a or Epac1, Reduces Protein Kinase A-Mediated Thyroid Cancer.

ABSTRACT:

Background

Thyroid cancer is an emerging health problem in the United States and worldwide. With incidence rates of thyroid cancer rapidly rising, the need to develop new treatment options is becoming a priority, and understanding the molecular mechanisms of this disease is crucial to furthering these efforts. Thyroid growth is driven by the TSH/cAMP/PKA signaling pathway, and it has previously been shown that activation of PKA through genetic ablation of the regulatory subunit Prkar1a (Prkar1a KO) is sufficient to cause follicular thyroid cancer in mouse models. cAMP also activates the Epac proteins and their downstream effectors, Rap1a and Rap1b.

Methods

Previously, the authors' laboratory generated a mouse model of follicular thyroid cancer by conferring thyroid-specific deletion of Prkar1a (R1a-TpoKO). To probe the roles of other components of the PKA signaling system in the development of thyroid cancer, this study deleted Rap1 and Epac1 in the setting of the Prkar1a knockout.

Results

Deletion of Rap1 significantly decreases thyroid size and cancer incidence in Prkar1a KO thyroids. Further, isoform-specific ablation of Rap1a and Rap1b implicates Rap1b as the downstream effector of PKA during thyroid carcinogenesis. In vivo modeling provides definitive evidence that Epac1 plays little role in thyroid proliferation and is dispensable for thyroid carcinogenesis arising from the deletion of Prkar1a.

Conclusions

This study demonstrate that PKA signaling to Rap1b is a key signaling node for follicular thyroid carcinogenesis, while Epac1 activity is not required for tumor development. This work sheds new light on the pathways involved in FTC development and identifies a possible target for the development of new therapies in the treatment of FTC.

SUBMITTER: Huk DJ

PROVIDER: S-EPMC6154455 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Deletion of Rap1b, but not Rap1a or Epac1, Reduces Protein Kinase A-Mediated Thyroid Cancer.

Huk Danielle J DJ Ashtekar Amruta A Magner Alexa A La Perle Krista K Kirschner Lawrence S LS

Thyroid : official journal of the American Thyroid Association 20180802 9

<h4>Background</h4>Thyroid cancer is an emerging health problem in the United States and worldwide. With incidence rates of thyroid cancer rapidly rising, the need to develop new treatment options is becoming a priority, and understanding the molecular mechanisms of this disease is crucial to furthering these efforts. Thyroid growth is driven by the TSH/cAMP/PKA signaling pathway, and it has previously been shown that activation of PKA through genetic ablation of the regulatory subunit Prkar1a ( ...[more]

PMID: 29882482

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Project description:RATIONALE:AMP-activated protein kinase (AMPK) has been reported to play a protective role in atherosclerosis. However, whether AMPK?2 controls atherosclerotic plaque stability remains unknown. OBJECTIVE:The aim of this study was to evaluate the impact of AMPK?2 deletion on atherosclerotic plaque stability in advanced atherosclerosis at the brachiocephalic arteries and to elucidate the underlying mechanisms. METHODS AND RESULTS:Features of atherosclerotic plaque stability and the markers for contractile or synthetic vascular smooth muscle cell (VSMC) phenotypes were monitored in the brachiocephalic arteries from Apoe(-/-)AMPK?2(-/-) mice or VSMC-specific AMPK?2(-/-) mice in an Apoe(-/-) background (Apoe(-/-)AMPK?2(sm-/-)) fed Western diet for 10 weeks. We identified that Apoe(-/-)AMPK?2(-/-) mice and Apoe(-/-)AMPK?2(sm-/-) mice exhibited similar unstable plaque features, aggravated VSMC phenotypic switching, and significant upregulation of Kruppel-like factor 4 (KLF4) in the plaques located in the brachiocephalic arteries compared with those found in Apoe(-/-) and Apoe(-/-)AMPK?2(sm+/+) control mice. Pravastatin, an AMPK activator, suppressed VSMC phenotypic switching and alleviated features of atherosclerotic plaque instability in Apoe(-/-)AMPK?2(sm+/+) mice, but not in Apoe(-/-)AMPK?2(sm-/-) mice. VSMC isolated from AMPK?2(-/-) mice displayed a significant reduction of contractile proteins(smooth muscle actin-?, calponin, and SM-MHC [smooth muscle-mysion heavy chain]) in parallel with increased detection of synthetic proteins (vimentin and osteopontin) and KLF4, as observed in vivo. KLF4-specific siRNA abolished AMPK?2 deletion-induced VSMC phenotypic switching. Furthermore, pharmacological or genetic inhibition of nuclear factor-?B significantly decreased KLF4 upregulation in VSMC from AMPK?2(-/-) mice. Finally, we found that AMPK?2 deletion markedly promoted the binding of nuclear factor-?Bp65 to KLF4 promoter. CONCLUSIONS:This study demonstrated that AMPK?2 deletion induces VSMC phenotypic switching and promotes features of atherosclerotic plaque instability in nuclear factor-?B-KLF4-dependent manner.

Dataset Information

Deletion of Rap1b, but not Rap1a or Epac1, Reduces Protein Kinase A-Mediated Thyroid Cancer.

Background

Methods

Results

Conclusions

Publications

Deletion of Rap1b, but not Rap1a or Epac1, Reduces Protein Kinase A-Mediated Thyroid Cancer.

Similar Datasets

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