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c-MYC: more than just a matter of life and death

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Key Points

Summary

  • The proto-oncogene c-MYC encodes a transcription factor that is implicated in various cellular processes ? cell growth, proliferation, loss of differentiation and apoptosis.

  • c-MYC activates a variety of known target genes as part of a heterodimeric complex with the protein MAX. For example, cyclin D2 and CDK2 are essential for cell-cycle progression, and translation initiation factors eIF4 and eIF2 are important in cell growth.

  • MYC?MAX heterodimers regulate gene activation through chromatin remodelling: association with co-activator TRRAP, which contains HAT activity, leads to acetylation of nucleosomal histones.

  • c-MYC inhibits the differentiation of many cell types. Conversely, MAD/MXI1 transcription factors promote differentiation by antagonizing c-MYC function by forming dimers with MAX. MAD?MAX dimers recruit corepressors (such as SIN3) and HDACs to target DNA, leading to histone deacetylation and subsequent repression of MYC target genes.

  • c-MYC sensitizes cells to a wide range of pro-apoptotic stimuli in vitro via cytochrome c release from mitochondria and subsequent formation of the apoptosome with APAF1 and procaspase-9.

  • Oncogenic c-MYC implies constitutive or deregulated expression of c-MYC that is no longer dependent on external signals and is associated with many human cancers.

  • Conditional transgenic mice, which allow regulated activation of c-MYC in distinct tissues (epidermis and pancreatic islets), have highlighted which cellular response attributed to c-MYC alone (proliferation or apoptosis) predominates in intact tissues in vivo.

  • Regulatable c-MYC transgenic mouse models of cancer have highlighted oncogenic properties of c-MYC in vivo when its apoptotic pathway is blocked, which include induction of angiogenesis, loss of cell?cell contacts and local tissue invasion.

  • Conditional mouse transgenic systems have ascertained when cancer-initiating oncogenic mutations (such as c-MYC and RAS) remain essential for maintenance of the established tumour in vivo. These findings are important for the development of candidate drug molecules that are directed against the oncoprotein.

Abstract

Deregulated expression of c-MYC occurs in a broad range of human cancers and is often associated with poor prognosis, indicating a key role for this oncogene in tumour progression. However, as established human tumours often bear multiple genetic lesions, it is difficult to determine whether c-MYC is instrumental in the initiation/progression of the tumour, or indeed whether inactivating c-MYC would lead to tumour regression. Regulatable transgenic mouse models of oncogenesis have shed light on these issues and provide hope for effective cancer therapies.

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Figure 1: Functional domains of human c-MYC protein.
Figure 2: c-MYC promotes G1?S progression through gene activation and repression.
Figure 3: MYC?MAX and MAD?MAX complexes regulate gene activation through chromatin remodelling.
Figure 4: Pathways involving c-MYC and apoptosis.
Figure 5: Suppression of c-MYC-induced apoptosis exposes several oncogenic properties of c-MYC.
Figure 6: Tumour regression following de-activation of initiating oncogenic lesion.

Change history

  • 08 October 2002

    Text accompanying certain citations was incorrectly placed (refs. 53, 55, 60, 84, 87, 92, 104, 119, 127, 135 in pdf and print) The text was moved to Refs. 54,56, 61, 87, 90, 97, 107, 126, 108, 111 respectively.

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Correspondence to Stella Pelengaris.

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DATABASES

Cancer.gov

acute myeloid leukaemia

breast cancer

Burkitt's lymphoma

cervical cancer

colon cancer

glioblastoma

melanoma

neuroblastoma

osteosarcoma

small-cell lung cancer

squamous-cell carcinoma

GenBank

adenovirus E1A

E6

E7

SV40 T antigen

FlyBase

dmyc

InterPro

bHLHZ domain

LocusLink

Apaf1

APAF1

Arf

ARF

BAD

BAX

Bcl2

BCL2

Bcl-xL

BCL-XL

Bmi1

CAD

caspase-2

caspase-3

caspase-6

caspase-7

caspase-8

caspase-9

caspase-10

CCND2

CD95

CDK2

CDK4

CUL1

cyclin D

cyclin E

cytochrome c

E2F1

E-cadherin

eIF2α

eIF4E

FADD

HDAC1

HDAC2

IGF1

INK4B

KIP1

Mad1

MAD1

MAD3

MAD4

MAX

MIZ1

MXI1

Mxi1

Myc

MYC

NF-κB

p300

p53

PDX1

Ras

RAS

Rb

RB

SP1

TERT

TGF-β

thrombospondin-1

TIP48

TIP49

TNF

TRAIL

TRRAP

VEGF

WAF1

Glossary

SURVIVAL FACTORS

Extracellular or intracellular molecules that block apoptosis. Extracellular molecules such as IGF1 mediate cell survival via its receptor, by activating the RAS?PI3K?AKT pathway.

PARACRINE

Secretion of factors from cells within a given tissue that influence neighbouring cells.

BCL2 FAMILY

A family of proteins that comprises both pro-apoptotic and anti-apoptotic members, the balance of which determines whether or not a cell commits apoptosis by regulating the release of cytochrome c from mitochondria.

BH-123 AND 'BH3-ONLY' PROTEINS

Pro-apoptotic members of the BCL2 family. BH-123 proteins share three of the BCL2 homology (BH) domains with the anti-apoptotic proteins, whereas 'BH3-only' proteins possess only the BH3 domain that is necessary for their pro-apoptotic activity.

CDKN2A

The CDKN2A locus encodes two structurally distinct proteins (INK4A and ARF) by reading a shared second exon in different translational reading frames. INK4A can induce cell-cycle arrest by binding to and preventing the ability of CDK4 and CDK6 to phosphorylate and functionally impair the tumour suppressor retinoblastoma. ARF prevents the degradation and inactivation of the tumour suppressor p53 by binding to MDM2, which might lead to cell-cycle arrest.

ANOIKIS

A form of apoptotic cell death that occurs after detachment from the extracellular matrix or from neighbouring cells. Loss of cell adhesion results in the loss of signalling pathways that mediate cell survival (such as via integrin or cadherin proteins).

RIP1?TAg2 MODEL

A transgenic mouse strain that expresses the simian virus T antigen (TAg) under the rat insulin II promoter (RIP) in the pancreatic islet β-cells. Carcinomas develop in the pancreatic islets cells and progress through characteristic stages.

LASER-CAPTURE MICRODISSECTION

An innovative technique that provides a simple and rapid method for the contamination-free selection of single cells or groups of cells from a wide variety of samples for DNA, RNA and protein analysis.

RT-PCR

(Real-time reverse transcription polymerase chain reaction). PCR using a fluorescent probe that contains a 5′-fluorescent label and 3′-quencher dye. As reverse transcription occurs, the 5′-reporter dye is released and the level of fluorescence emission can be measured as the reaction is proceeding. This technique can be used throughout a patient's treatment programme to monitor the proportion of leukaemic cells that still carry a translocation-induced fusion mRNA.

TOPONOMICS

Definition of protein expression/concentration in the context of cellular location ? for example, on a histological tissue section.

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Pelengaris, S., Khan, M. & Evan, G. c-MYC: more than just a matter of life and death. Nat Rev Cancer 2, 764–776 (2002). https://doi.org/10.1038/nrc904

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