Diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) are the two potent secondary messengers generated by the activated PIP2-specific PLC (i.e., phosphatidyl inositol 4,5 bisphosphate- specific phospholipase C) that cleaves PIP2 to produce these two secondary messengers. Both DAG and IP3 contribute to the activation of protein-kinase C i.e., PKC.
The IP3 binds to the endoplasmic reticulum (ER) on the Ca2+ channels, causing them to open. SERCA pumps ensures that the cytosolic Ca2+ level is less than ER Ca2+ levels, so when these Ca2+ channel opens, Ca2+ rushes out thus increasing cytosolic Ca2+ levels to about 10^-6 M.
This elevated Ca2+ levels leads to the activation of PKC. DAG cooperates with Ca2+ in activating PKC, thus also acting as a secondary messenger. Activation involves the movement of PKC domain away from its location in the substrate- binding region of the enzyme, allowing the enzyme to bind and phosphorylate proteins that contain a PKC consensus sequences, ser or thr residue recognized by PKC.
Now, Phorbal esters acts as analogs of DAG, so they have the ability to stimulate PKC.
Phorbal esters are potent tumor promoters. By activating PKC they activate other intracellular targets, including cascade of protein kinase known as the MAP kinase pathway, leading to transcription factor phosphorylation, changes in the gene expression and stimulate cell proliferation, hence promoting tumor growth.
The IP3 binds to the endoplasmic reticulum (ER) on the Ca2+ channels, causing them to open. SERCA pumps ensures that the cytosolic Ca2+ level is less than ER Ca2+ levels, so when these Ca2+ channel opens, Ca2+ rushes out thus increasing cytosolic Ca2+ levels to about 10^-6 M.
This elevated Ca2+ levels leads to the activation of PKC. DAG cooperates with Ca2+ in activating PKC, thus also acting as a secondary messenger. Activation involves the movement of PKC domain away from its location in the substrate- binding region of the enzyme, allowing the enzyme to bind and phosphorylate proteins that contain a PKC consensus sequences, ser or thr residue recognized by PKC.
Now, Phorbal esters acts as analogs of DAG, so they have the ability to stimulate PKC.
Phorbal esters are potent tumor promoters. By activating PKC they activate other intracellular targets, including cascade of protein kinase known as the MAP kinase pathway, leading to transcription factor phosphorylation, changes in the gene expression and stimulate cell proliferation, hence promoting tumor growth.
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