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Transcription factors as targets for cancer therapy

Key Points

Summary

  • Signalling proteins, which are often mutated in cancer, change transcription patterns.

  • Many more signalling proteins are affected in cancer than transcription factors, electing transcription factors as cogent targets.

  • One or more latent cytoplasmic transcription factors (such as STATs, NF-κB, β-catenin and Notch intracellular domain (NICD)) have increased activity in most human cancers, and in many cases prevent apoptosis of cancer cells.

  • Necessary physical interaction among transcription factors and cofactors in the nucleus affords selective sites of potential drug action.

  • Should pharmacology of transcription-factor inhibition be the wave of the future? It might be difficult, but it should not be impossible.

Abstract

A limited list of transcription factors are overactive in most human cancer cells, which makes them targets for the development of anticancer drugs. That they are the most direct and hopeful targets for treating cancer is proposed, and this is supported by the fact that there are many more human oncogenes in signalling pathways than there are oncogenic transcription factors. But how could specific transcription-factor activity be inhibited?

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Figure 1: Generalized signalling pathway.
Figure 2: WNT signals through β-catenin.

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DATABASES

Cancer.gov

brain cancer

breast cancer

colon cancer

head and neck cancer

hepatocellular carcinoma

Hodgkin's disease

leukaemia

lymphomas

medulloblastoma

multiple myeloma

prostate cancer

rhabdomyosarcomas

skin cancer

small-cell lung cancer

FlyBase

Armadillo

Delta

Dishevelled

Hedgehog

ptc

Serrate

smo

LocusLink

A2M

ABL

APC

β-catenin

γ-catenin

CBP

CREB

CREM

Delta-like

E2F1

E2F2

E2F3

E-cadherin

EGF

EGFR

FOS

Frizzled

GLI1

GLI2

GLI3

GR

GSK3β

HMG1

BCL9

IκB

IL-1

IL-6

IRF3

Jagged

JAK

JUN

JUNB

JUND

MAX

MYC

NF-κB

Notch1

Notch2

Notch3

Notch4

p53

p300

PDGFR

PIAS3

PU.1

RAS

RB

SP1

SRC

STAT1

STAT3

STAT4

STAT5

TCF4

TGF-β

TNF-α

WNT

<i>Saccharomyces</i> Genome Database

GCN4

Glossary

SRC-LIKE

The generic name for proteins that are similar to v-src, the oncogene of Rous sarcoma virus.

SH2 DOMAIN

(Src homology 2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

ANKYRIN REPEATS

Short amino-acid repeats that were first identified in the protein ankyrin, to which a number of cytoplasmic proteins bind.

IMPORTIN(S)

A family of proteins (also called karyopherins) that combine with 'cargo' proteins in the cytoplasm and engage the nuclear import machinery to bring proteins into the nucleus.

ENHANCEOSOME

A group of transcription factors that are bound to regulatory DNA elements that act in concert to activate gene transcription.

REED–STERNBERG CELLS

Characteristic large stellate lymph-node cells that are associated with Hodgkin's disease.

PROTO-ONCOGENES

Normal cellular genes that, when mutant or overactive, contribute to cancerous transformation in cells.

REL PROTEINS

Family name for a group of proteins that have sequence similarity to the oncogene in the chicken virus (v-rel) that causes reticulo-endothelial tumours.

WINGLESS

(Wg). The gene discovered early in Drosophila genetics that encodes a protein that is very similar to a DNA integrase named Int that is encoded by a retrovirus. The original term Int was melded with Wg to produce the current term WNT.

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Darnell, J. Transcription factors as targets for cancer therapy. Nat Rev Cancer 2, 740–749 (2002). https://doi.org/10.1038/nrc906

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