scholarly journals Cyclic 3′,5′-guanosine monophosphate-dependent protein kinase inhibits colon cancer cell adaptation to hypoxia

Cancer ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 5282-5293 ◽  
Author(s):  
In-Kiu Kwon ◽  
Rui Wang ◽  
Nikhil Prakash ◽  
Renee Bozard ◽  
Troy A. Baudino ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Protein Kinase ◽  
Cancer Cell ◽  
Colon Cancer Cell ◽  
Guanosine Monophosphate ◽  
Adaptation To Hypoxia ◽  
Dependent Protein Kinase ◽  
Cell Adaptation ◽  
Dependent Protein

scholarly journals The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia

2020 ◽  
Vol 22 (1) ◽  
pp. 52
Author(s):  
Mirja Koch ◽  
Constanze Scheel ◽  
Hongwei Ma ◽  
Fan Yang ◽  
Michael Stadlmeier ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mouse Model ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Cone Photoreceptor ◽  
Photoreceptor Degeneration ◽  
Dependent Protein Kinase ◽  
Genetic Ablation ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

Mutations in the CNGA3 gene, which encodes the A subunit of the cyclic guanosine monophosphate (cGMP)-gated cation channel in cone photoreceptor outer segments, cause total colour blindness, also referred to as achromatopsia. Cones lacking this channel protein are non-functional, accumulate high levels of the second messenger cGMP and degenerate over time after induction of ER stress. The cell death mechanisms that lead to loss of affected cones are only partially understood. Here, we explored the disease mechanisms in the Cnga3 knockout (KO) mouse model of achromatopsia. We found that another important effector of cGMP, the cGMP-dependent protein kinase 2 (Prkg2) is crucially involved in cGMP cytotoxicity of cones in Cnga3 KO mice. Virus-mediated knockdown or genetic ablation of Prkg2 in Cnga3 KO mice counteracted degeneration and preserved the number of cones. Analysis of markers of endoplasmic reticulum stress and unfolded protein response confirmed that induction of these processes in Cnga3 KO cones also depends on Prkg2. In conclusion, we identified Prkg2 as a novel key mediator of cone photoreceptor degeneration in achromatopsia. Our data suggest that this cGMP mediator could be a novel pharmacological target for future neuroprotective therapies.

Type 2 cGMP-dependent protein kinase regulates proliferation and differentiation in the colonic mucosa

2012 ◽  
Vol 303 (2) ◽  
pp. G209-G219 ◽  
Author(s):  
Rui Wang ◽  
In-Kiu Kwon ◽  
Muthusamy Thangaraju ◽  
Nagendra Singh ◽  
Kebin Liu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Colon Cancer Cell ◽  
Tissue Homeostasis ◽  
Colon Cancer Cells ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Colon Cancer Cell Lines ◽  
Proliferation And Differentiation ◽  
Dependent Protein

Signaling through cGMP has emerged as an important regulator of tissue homeostasis in the gastrointestinal tract, but the mechanism is not known. Type 2 cGMP-dependent protein kinase (PKG2) is a major cGMP effector in the gut epithelium, and the present studies have tested its importance in the regulation of proliferation and differentiation in the mouse colon and in colon cancer cell lines. Tissue homeostasis was examined in the proximal colon of Prkg2 −/− mice using histological markers of proliferation and differentiation. The effect of ectopic PKG2 on proliferation and differentiation was tested in vitro using inducible colon cancer cell lines. PCR and luciferase reporter assays were used to determine the importance of Sox9 downstream of PKG2. The colons of Prkg2 −/− mice exhibited crypt hyperplasia, increased epithelial apoptosis, and reduced numbers of differentiated goblet and enteroendocrine cells. Ectopic PKG2 was able to inhibit proliferation and induce Muc2 and CDX2 expression in colon cancer cells, but did not significantly affect cell death. PKG2 reduced Sox9 levels and signaling, suggesting possible involvement of this pathway downstream of cGMP in the colon. The work presented here demonstrates a novel antiproliferative and prodifferentiation role for PKG2 in the colon. These homeostatic functions of PKG2 were reproducible in colon cancer cells lines where downregulation of Sox9 is a possible mechanism. The similarities in phenotype between PKG2 and GCC knockout mice positions PKG2 as a likely mediator of the homeostatic effects of cGMP signaling in the colon.

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