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Connecting proliferation and apoptosis in development and disease

Key Points

  • Signals that trigger cell proliferation also trigger programmed cell death. This functions as a protective mechanism against cancer. Control of proliferation-induced cell death is also essential to permit normal tissue growth during development.

  • The Myc proteins have a central role in controlling cell and tissue growth in animals. Myc mutant animals are small.

  • In multicellular tissues, cells compete with one another for growth and survival cues. Myc activity affects the ability of cells to compete. Evidence has begun to accumulate that cell competition has an important role in the control of tissue growth during Drosophila melanogaster development. At present, nothing is known about whether competition has a comparable role in vertebrate development, although this seems likely.

  • Genetic screens for loci affecting tissue growth in D. melanogaster have identified new genes that simultaneously promote proliferation and inhibit apoptosis (or vice versa). Mutations in several of the mammalian orthologues have been linked to specific cancers.

Abstract

Cells grow and divide rapidly during embryonic and postnatal development. Net tissue growth reflects the balance between the addition of new cells and the elimination of existing cells by programmed cell death. Cells compete for growth and survival factors to ensure an appropriate balance between the addition and elimination of cells. Elaborate mechanisms ensure that cells do not evade these constraints, and thereby prevent uncontrolled proliferation.

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Figure 1: Myc regulation of G1–S progression.
Figure 2: Simplified model of intrinsic and extrinsic apoptosis pathways.
Figure 3: The ARF–MDM2–p53 response to activated oncogenes.
Figure 4: Slik-driven growth is opposed by apoptosis.
Figure 5: The Hippo–Salvador–Warts complex suppresses tissue growth.
Figure 6: Involvement of the Hippo–Salvador–Warts complex in apoptosis and proliferation.

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Acknowledgements

The authors would like to thank L. Johnston for kindly sharing results before publication, and J. Brennecke, S. Pizette, S. Szuplewski, D. Neubueser and M. Treier for discussions, comments and suggestions.

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DATABASES

Entrez

ARF

MDM2

Myc

slik

Flybase

bantam

brinker

Hid

Hippo

salvador

Slik

warts

Wingless

SwissProt

c-Myc

L-Myc

N-Myc

p53

PUMA

Glossary

CELL GROWTH

An increase in cell mass.

ONCOGENE

A gene that is causally linked to the formation of tumours in vivo, usually as a result of mutant forms of the gene.

BASIC HELIX–LOOP–HELIX LEUCINE-ZIPPER PROTEIN

A type of transcription factor with a basic domain, a 'helix–loop–helix' DNA-binding motif and a 'leucine zipper' dimerization domain.

CYCLINS

A family of proteins, the levels of which fluctuate throughout the cell cycle. By activating cyclin-dependent kinases, they regulate the cell cycle. D- and E-type cyclins promote G1–S phase progression; A- and B-type cyclins regulate S–G2–M progression.

E2F PROTEINS

Members of a family of transcription factors that control the expression of genes that are involved in cell-cycle progression, including cyclin E, string CDC25 phosphatase and components of the DNA-synthesis machinery.

WING IMAGINAL DISCS

Imaginal discs are the larval precursors of adult structures. The wing imaginal discs make the dorsal thorax and the wing appendages.

HYPOMORPHIC

A mutation that reduces, but does not completely eliminate, the function of a gene.

PRIMARY CELLS

Cultured cells that are derived directly from tissue (often embryonic tissue). They are distinct from transformed cell lines.

CELL-SIZE CHECKPOINT

A mechanism that ensures that cells divide at a defined size.

MINUTE MUTATIONS

A class of mutations that produce a dominant growth defect. Minutes are caused by the mutation of genes that encode any of several ribosomal proteins.

BH3-ONLY DOMAIN PROTEINS

Members of a class of pro-apoptotic proteins in the larger BCL2 family that contain a single 'BCL2 homology-3' domain.

EXTRINSIC DEATH PATHWAY

An apoptotic signalling pathway that is activated by binding of secreted ligands to 'death receptors' of the tumour-necrosis-factor-receptor family.

MITOGENIC

Promotes cell proliferation.

INTRINSIC DEATH PATHWAY

An apoptotic signalling pathway that is activated in response to various forms of intracellular stress.

BCL2

An anti-apoptotic protein. It is the founding member of the BCL2 family of pro- and anti-apoptotic proteins.

E3 UBIQUITIN PROTEIN LIGASE

An enzyme that catalyses the addition of ubiquitin to target proteins, which signals their degradation via the proteasome pathway.

WNT PROTEINS

A family of highly conserved secreted signalling molecules that regulate cell–cell interactions during embryogenesis.

STERILE 20 KINASE

A member of a diverse family of serine/threonine protein kinases that share homology with the yeast Ste20 kinase.

microRNA

A small RNA of 22 nucleotides that is encoded by an endogenous gene. The microRNA regulates expression of RNAs to which it is complementary in sequence.

ORTHOLOGUE

Functionally related genes with extensive sequence similarity, which indicates a common ancestor. Orthologues are often used to indicate the most closely related members of larger gene families in different species.

WW DOMAIN

A protein domain that is involved in binding to proline-rich peptide motifs.

SCAFFOLD

A protein that functions as a support to assemble a multiprotein complex.

CELL COMPETITION

A phenomenon that is observed in imaginal discs — slowly dividing cells are eliminated by apoptosis owing to competition with faster-dividing cells.

GENETIC MOSAICS

Tissues that are composed of cells of different genotypes. They are usually generated by controlled recombination during mitosis.

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Hipfner, D., Cohen, S. Connecting proliferation and apoptosis in development and disease. Nat Rev Mol Cell Biol 5, 805–815 (2004). https://doi.org/10.1038/nrm1491

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