Limits...
Serine 204 phosphorylation and O-β-GlcNAC interplay of IGFBP-6 as therapeutic indicator to regulate IGF-II functions in viral mediated hepatocellular carcinoma.

Ahmad W, Shabbiri K, Ijaz B, Asad S, Nazar N, Nazar S, Fouzia K, Kausar H, Gull S, Sarwar MT, Shahid I, Hassan S - Virol. J. (2011)

Bottom Line: In HCV, core protein is believed to trans-activate host IGF-II receptor through PKC pathway and the inhibition of tumor cell growth can be achieved by blocking IGF-II pathway either at transcriptional level or increasing its binding with IGFBPs (Insulin like growth factor proteins) at C-terminal, so that it is not available in free form.IGFBP-6 is a specific inhibitor of IGF-II actions.Phosphorylation of IGFBPs inhibits IGFs action on target cells while O-glycosylation prevents binding of IGFBP-6 to glycosaminoglycans and cell membranes and resulting in a 10-fold higher affinity for IGF-II.

View Article: PubMed Central - HTML - PubMed

Affiliation: Applied and Functional Genomics Lab, Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.

ABSTRACT
Hepatocellular carcinoma is mainly associated with viral hepatitis B and C. Activation of cell growth stimulator IGF-II gene is observed in tumor formation especially in viral associated hepatocellular carcinoma. Elevated IGF-II levels are indicator of increased risk for cholangiocellular and hepatocellular carcinomas through over saturation of IGF-II binding capacities with IGF receptors leading to cellular dedifferentiation. In HCV, core protein is believed to trans-activate host IGF-II receptor through PKC pathway and the inhibition of tumor cell growth can be achieved by blocking IGF-II pathway either at transcriptional level or increasing its binding with IGFBPs (Insulin like growth factor proteins) at C-terminal, so that it is not available in free form. IGFBP-6 is a specific inhibitor of IGF-II actions. Affinity of IGFBPs with IGFs is controlled by post-translational modifications. Phosphorylation of IGFBPs inhibits IGFs action on target cells while O-glycosylation prevents binding of IGFBP-6 to glycosaminoglycans and cell membranes and resulting in a 10-fold higher affinity for IGF-II. O-glycosylation and phosphorylation operate the functional expression of cellular proteins, this switching on and off the protein expression is difficult to monitor in vivo. By using neural network based prediction methods, we propose that alternate O-β-GlcNAc modification and phosphorylation on Ser 204 control the binding of IGFBP-6 with IGF-II. This information may be used for developing new therapies by regulating IGFBP-6 assembly with IGF-II to minimize the risk of viral associated hepatocellular carcinoma. We can conclude that during HCV/HBV infection, O-β-GlcNAc of IGFBP-6 at Ser 204 diminish their binding with IGF-II, increase IGF-II cellular expression and promote cancer progression which can lead to hepatocellular carcinoma. Furthermore, this site can be used for developing new therapies to control the IGF-II actions during viral infection to minimize the risk of hepatocellular carcinoma.

Show MeSH

Related in: MedlinePlus

Multiple alignments of six vertebrates sequences (Human, Bovin, Sheep, Pig, Mouse and Rat). These different sequences were ordered as aligned results from ClustalW. The consensus sequence is marked by an asterisk, conserved substitution by a double dot, and semi conserved substitution by a single dot.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3108323&req=5

Figure 1: Multiple alignments of six vertebrates sequences (Human, Bovin, Sheep, Pig, Mouse and Rat). These different sequences were ordered as aligned results from ClustalW. The consensus sequence is marked by an asterisk, conserved substitution by a double dot, and semi conserved substitution by a single dot.

Mentions: To determine conserved and conserved substituted Ser and Thr residues within each subtype, human IGFBP-6 protein FASTA sequence was aligned with other mammals (Figure 1). It is clear from the figure that Ser 120, 144, 169, 203, 204, 225 and 239; and Thr 143 and 176 were highly conserved in mammals. Meanwhile, Ser 231 and 232; and Thr 75, 126, 145, 146 and 236 showed conserved substitutions within mammals.


Serine 204 phosphorylation and O-β-GlcNAC interplay of IGFBP-6 as therapeutic indicator to regulate IGF-II functions in viral mediated hepatocellular carcinoma.

Ahmad W, Shabbiri K, Ijaz B, Asad S, Nazar N, Nazar S, Fouzia K, Kausar H, Gull S, Sarwar MT, Shahid I, Hassan S - Virol. J. (2011)

Multiple alignments of six vertebrates sequences (Human, Bovin, Sheep, Pig, Mouse and Rat). These different sequences were ordered as aligned results from ClustalW. The consensus sequence is marked by an asterisk, conserved substitution by a double dot, and semi conserved substitution by a single dot.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108323&req=5

Figure 1: Multiple alignments of six vertebrates sequences (Human, Bovin, Sheep, Pig, Mouse and Rat). These different sequences were ordered as aligned results from ClustalW. The consensus sequence is marked by an asterisk, conserved substitution by a double dot, and semi conserved substitution by a single dot.
Mentions: To determine conserved and conserved substituted Ser and Thr residues within each subtype, human IGFBP-6 protein FASTA sequence was aligned with other mammals (Figure 1). It is clear from the figure that Ser 120, 144, 169, 203, 204, 225 and 239; and Thr 143 and 176 were highly conserved in mammals. Meanwhile, Ser 231 and 232; and Thr 75, 126, 145, 146 and 236 showed conserved substitutions within mammals.

Bottom Line: In HCV, core protein is believed to trans-activate host IGF-II receptor through PKC pathway and the inhibition of tumor cell growth can be achieved by blocking IGF-II pathway either at transcriptional level or increasing its binding with IGFBPs (Insulin like growth factor proteins) at C-terminal, so that it is not available in free form.IGFBP-6 is a specific inhibitor of IGF-II actions.Phosphorylation of IGFBPs inhibits IGFs action on target cells while O-glycosylation prevents binding of IGFBP-6 to glycosaminoglycans and cell membranes and resulting in a 10-fold higher affinity for IGF-II.

View Article: PubMed Central - HTML - PubMed

Affiliation: Applied and Functional Genomics Lab, Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.

ABSTRACT
Hepatocellular carcinoma is mainly associated with viral hepatitis B and C. Activation of cell growth stimulator IGF-II gene is observed in tumor formation especially in viral associated hepatocellular carcinoma. Elevated IGF-II levels are indicator of increased risk for cholangiocellular and hepatocellular carcinomas through over saturation of IGF-II binding capacities with IGF receptors leading to cellular dedifferentiation. In HCV, core protein is believed to trans-activate host IGF-II receptor through PKC pathway and the inhibition of tumor cell growth can be achieved by blocking IGF-II pathway either at transcriptional level or increasing its binding with IGFBPs (Insulin like growth factor proteins) at C-terminal, so that it is not available in free form. IGFBP-6 is a specific inhibitor of IGF-II actions. Affinity of IGFBPs with IGFs is controlled by post-translational modifications. Phosphorylation of IGFBPs inhibits IGFs action on target cells while O-glycosylation prevents binding of IGFBP-6 to glycosaminoglycans and cell membranes and resulting in a 10-fold higher affinity for IGF-II. O-glycosylation and phosphorylation operate the functional expression of cellular proteins, this switching on and off the protein expression is difficult to monitor in vivo. By using neural network based prediction methods, we propose that alternate O-β-GlcNAc modification and phosphorylation on Ser 204 control the binding of IGFBP-6 with IGF-II. This information may be used for developing new therapies by regulating IGFBP-6 assembly with IGF-II to minimize the risk of viral associated hepatocellular carcinoma. We can conclude that during HCV/HBV infection, O-β-GlcNAc of IGFBP-6 at Ser 204 diminish their binding with IGF-II, increase IGF-II cellular expression and promote cancer progression which can lead to hepatocellular carcinoma. Furthermore, this site can be used for developing new therapies to control the IGF-II actions during viral infection to minimize the risk of hepatocellular carcinoma.

Show MeSH
Related in: MedlinePlus