Title |
Cancer-Associated Protein Kinase C Mutations Reveal Kinase’s Role as Tumor Suppressor
|
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Published in |
Cell, January 2015
|
DOI | 10.1016/j.cell.2015.01.001 |
Pubmed ID | |
Authors |
Corina E. Antal, Andrew M. Hudson, Emily Kang, Ciro Zanca, Christopher Wirth, Natalie L. Stephenson, Eleanor W. Trotter, Lisa L. Gallegos, Crispin J. Miller, Frank B. Furnari, Tony Hunter, John Brognard, Alexandra C. Newton |
Abstract |
Protein kinase C (PKC) isozymes have remained elusive cancer targets despite the unambiguous tumor promoting function of their potent ligands, phorbol esters, and the prevalence of their mutations. We analyzed 8% of PKC mutations identified in human cancers and found that, surprisingly, most were loss of function and none were activating. Loss-of-function mutations occurred in all PKC subgroups and impeded second-messenger binding, phosphorylation, or catalysis. Correction of a loss-of-function PKCβ mutation by CRISPR-mediated genome editing in a patient-derived colon cancer cell line suppressed anchorage-independent growth and reduced tumor growth in a xenograft model. Hemizygous deletion promoted anchorage-independent growth, revealing that PKCβ is haploinsufficient for tumor suppression. Several mutations were dominant negative, suppressing global PKC signaling output, and bioinformatic analysis suggested that PKC mutations cooperate with co-occurring mutations in cancer drivers. These data establish that PKC isozymes generally function as tumor suppressors, indicating that therapies should focus on restoring, not inhibiting, PKC activity. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 5 | 33% |
Spain | 2 | 13% |
United Kingdom | 1 | 7% |
Japan | 1 | 7% |
Tunisia | 1 | 7% |
Unknown | 5 | 33% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 8 | 53% |
Scientists | 6 | 40% |
Practitioners (doctors, other healthcare professionals) | 1 | 7% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 3 | 1% |
United Kingdom | 2 | <1% |
Japan | 1 | <1% |
Unknown | 288 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 54 | 18% |
Researcher | 49 | 17% |
Student > Bachelor | 34 | 12% |
Student > Master | 28 | 10% |
Student > Doctoral Student | 15 | 5% |
Other | 53 | 18% |
Unknown | 61 | 21% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 75 | 26% |
Agricultural and Biological Sciences | 74 | 25% |
Medicine and Dentistry | 18 | 6% |
Chemistry | 18 | 6% |
Pharmacology, Toxicology and Pharmaceutical Science | 13 | 4% |
Other | 24 | 8% |
Unknown | 72 | 24% |