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Oncogenic PI3K deregulates transcription and translation

Key Points

  • Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that generate second messengers that govern cellular activities and properties including proliferation, survival, motility and morphology.

  • PIK3CA, the gene that encodes the catalytic subunit p110a of PI3K, is frequently mutated in human solid tumours.

  • Cancer-specific mutations are clustered in the helical and the kinase domains of p110a. The amino-acid residues E542, E545 and H1047 are prominent mutational hot spots.

  • The mutations in the p110a hot spots induce a gain of enzymatic function and confer oncogenic activity both in vitro and in vivo.

  • The oncogenicity of PI3K is the result of interactions with transcriptional and translational controls.

Abstract

There have long been indications of a role for PI3K (phosphatidylinositol 3-kinase) in cancer pathogenesis. Experimental data document a requirement for deregulation of both transcription and translation in PI3K-mediated oncogenic transformation. The recent discoveries of cancer-specific mutations in PIK3CA, the gene that encodes the catalytic subunit p110α of PI3K, have heightened the interest in the oncogenic potential of this lipid kinase and have made p110α an ideal drug target.

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Figure 1: PI3Ks constitute a family of enzymes that is divided into three classes.
Figure 2: PI3K–AKT signalling affects translation and transcription.
Figure 3: Point mutations in PIK3CA observed in human tumours.

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Acknowledgements

The work of the authors is supported by grants from the National Cancer Institute.

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DATABASES

National Cancer Institute

Breast cancer

Colorectal cancer

Ovarian cancer

Pancreatic cancer

Swiss-Prot

4EBP

AKT

AP1

BAD

β-catenin

caspase 9

c-MYC

COT

CRM1

cyclin D1

cyclin D2

DNA-PK

EGFR

ERBB2

FKBP12

FOXO1

FOXO3A

FOXO4

FOXO6

GSK3

HIF1α

IKK

ILK

MDM2

MIZ1

NFκB

p21cip1

p27kip1

p53

PDK1

PTEN

REL-A

RHEB

S6K

SKP2

SMAD

YB-1

FURTHER INFORMATION

Atlas of Genetics and Cytogenetics in Oncology and Haematology (PIK3CA)

Peter K. Vogt's homepage

The PI3K–PTEN–AKT signalling pathway

Glossary

SH2 DOMAIN

A protein domain, homologous to an equivalent domain in the SRC protein, that facilitates protein–protein interactions by binding to tyrosine-phosphorylated protein sequences.

PLECKSTRIN HOMOLOGY DOMAIN

A protein domain that was originally identified in the protein pleckstrin that forms a phospholipid-binding pocket and in particular binds to PIP3.

MACROLIDE

A group of antibiotics that are produced by various strains of Streptomyces and have a complex macrocyclic structure.

POL I- AND POL III-DEPENDENT TRANSCRIPTION

Class I RNA polymerases synthesize all ribosomal RNAs except the 5S ribosomal RNA; class III RNA polymerases transcribe transfer RNA genes and the gene that encodes the 5S ribosomal RNA.

mRNA CAP STRUCTURE

The 5′ end of virtually all mRNAs is protected by a 'cap' with the chemical structure m7GpppN (where m7G represents 7-methylguanylate, p represents a phosphate group and N represents any base).

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Bader, A., Kang, S., Zhao, L. et al. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 5, 921–929 (2005). https://doi.org/10.1038/nrc1753

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