Premium
Reversing The Paradigm: Protein Kinase C As A Tumor Suppressor
Author(s) -
Newton Alexandra
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.510.1
Subject(s) - protein kinase c , suppressor , loss function , carcinogenesis , isozyme , kinase , function (biology) , cancer research , receptor , phosphorylation , biology , second messenger system , signal transduction , microbiology and biotechnology , phenotype , mutation , cancer , enzyme , biochemistry , genetics , gene
Protein kinase C (PKC) isozymes transduce the myriad of signals resulting from receptor mediated hydrolysis of phospholipids, playing critical roles in diverse cellular functions. Its activity must be precisely tuned for cellular homeostasis and too much, or not enough, activity results in pathophysiologies. The discovery in the 1980s that PKCs are receptors for the potent tumor promoting phorbol esters led to the dogma that activation of PKC by phorbol esters promotes tumorigenesis. However, clinical trials with PKC inhibitors have not have not only failed but, in some cases, resulted in worsened outcome. Analysis of approximately 10% of the >500 mutations identified in human cancers reveals that most mutations are loss‐of‐function and none are activating. Loss‐of‐function mutations occur in all PKC subgroups and occur by disrupting diverse mechanisms: they impede second‐messenger binding, prevent phosphorylation, or inhibit catalysis. Thus, PKC functions as a tumor suppressor and its loss of confers a survival advantage. In contrast, we show that gain‐of‐function mutations accompany degenerative diseases such as Alzheimer's disease. Our results reveal that therapeutic strategies should focus on restoring PKC activity in cancer and inhibiting its activity in neurodegenerative diseases. Support or Funding Information NIH GM43154