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Cell death in mammalian cell culture: molecular mechanisms and cell line engineering strategies

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Abstract

Cell death is a fundamentally important problem in cell lines used by the biopharmaceutical industry. Environmental stress, which can result from nutrient depletion, by-product accumulation and chemical agents, activates through signalling cascades regulators that promote death. The best known key regulators of death process are the Bcl-2 family proteins which constitute a critical intracellular checkpoint of apoptosis cell death within a common death pathway. Engineering of several members of the anti-apoptosis Bcl-2 family genes in several cell types has extended the knowledge of their molecular function and interaction with other proteins, and their regulation of cell death. In this review, we describe the various modes of cell death and their death pathways at molecular and organelle level and discuss the relevance of the growing knowledge of anti-apoptotic engineering strategies to inhibit cell death and increase productivity in mammalian cell culture.

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Abbreviations

A1:

Apolipoprotein

AIF:

Apoptosis-inducing factors

ANT:

Adenine nucleotide translocator

Akt:

Protein kinase B

Atgs:

Autophagy-related proteins

Aven:

Apoptosis, caspase activation inhibitor

Apaf1:

Apoptotic protease activation factor 1

Ap1:

Jun oncogene

Bad:

Bcl-2-associated agonist of cell death

Bak:

Bcl-2-antagonist/killer 1

Bax:

Bcl-2-associated X protein

Bcl-2:

B-cell lymphoma

Bcl-xL:

Bcl-2 related gene, long isoform

Bid:

BH3 interacting domain death agonist

Bim:

Bcl-2-like 11

Bok:

Bcl-2-related ovarian killer

c-MYC:

v-myc myelocytomatosis viral oncogene homolog

Creb:

AMP responsive element binding protein 1

ER:

Endoplasmic reticulum

E2F4:

Eukaryotic transcription factor 4

E2F1:

Eukaryotic transcription factor 1

FADD:

Fas-associated death domain

FasL:

Fas ligand

Mcl-1:

Myeloid cell leukemia sequence 1 (Bcl2-related)

mTOR:

Target of rapamycin

MOMP:

Mitochondrial outer membrane permeabilization

Noxa:

PMA-induced protein

NUR77:

Nuclear receptor subfamily 4

PI3K:

Phosphoinositide 3-kinase

PKB:

Protein kinase B

PT:

Permeability transition pores

PUMA:

p53-upregulated modulator of apoptosis

p27:

Cyclin dependent kinase inhibitor protein 1B

SMAC/DIABLO:

Second mitochondria-derived activator of caspases/direct IAP-bind protein with low pI

TNF:

Tumour necrosis factor

TRAIL:

TNF-related apoptosis-inducing ligand

VDAC:

Voltage dependent anion channel

UPR:

Unfolded protein response

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  1. School of Chemical and Bioprocess Engineering, and Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Republic of Ireland

    Britta Krampe & Mohamed Al-Rubeai

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Krampe, B., Al-Rubeai, M. Cell death in mammalian cell culture: molecular mechanisms and cell line engineering strategies. Cytotechnology 62, 175–188 (2010). https://doi.org/10.1007/s10616-010-9274-0

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