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  • Review Article
  • Published:

The role of the RB tumour suppressor pathway in oxidative stress responses in the haematopoietic system

Nature Reviews Cancer volume 8, pages 769–781 (2008)Cite this article

Key Points

  • Reactive oxygen species (ROS) produced at the mitochondrial respiratory chain and to a lesser extent by peroxisomes and plasma membrane-bound NADPH oxidases have a crucial role in signalling pathways in the cell, including a requirement for ROS to promote S phase entry.

  • Excess ROS can lead to cell cycle arrest, senescence or cell death and thus proper management of ROS is required to prevent premature ageing and disease.

  • Increased ROS levels in the haematopoietic system lead to stem cell depletion and bone marrow failure and are associated with activation of the retinoblastoma (RB) pathway through induction of the cyclin-dependent kinase inhibitor INK4A.

  • RB is required to maintain the haematopoietic stem cell (HSC) pool and prevent aberrant S phase entry of HSCs in response to proliferative stress.

  • Defects in Rb1-deficient haematopoiesis are due in part to non-cell-autonomous events, including the influence of the bone marrow niche on the development of myeloproliferative disease and the sensitivity of stem cells and erythroid cells to proliferative stress. These observations are indicative of a role for RB in regulating the stromal microenvironment.

  • Disruption of ataxia telangiectasia mutated (ATM) or the Forkhead box O (Foxo) transcription factors in mice leads to increased ROS levels in HSCs that induce p38 mitogen-activated protein kinase activity, INK4A expression, downregulation of N-cadherin and increased stem cell recruitment into the cell cycle, probably due to reduced expression of the cyclin-dependent kinase inhibitors p21 and p27. Thus, ATM and Foxo act upstream of RB in the response of the cell to ROS.

  • Proliferative stress also induces erythroid maturation defects in the Rb1-null mouse that include failure to exit the cell cycle during terminal differentiation, increased ROS levels, increased DNA damage and altered management of mitochondrial mass.

  • Acetylation of RB modulates its rate of turnover in response to oxidative stress and protein phosphatase 2A-dependent dephosphorylation modulates its activity.

  • The role of the RB pathway in responding to oxidative stress in the haematopoietic system has implications for how other cell types respond to ROS, including human tumours that lack a functional RB pathway. Such cancers exhibit defective stress responses and increased levels of ROS, making them more susceptible to chemotherapy-induced death.

Abstract

Exposure to pro-oxidants and defects in the repair of oxidative base damage are associated with disease and ageing and also contribute to the development of anaemia, bone marrow failure and haematopoietic malignancies. This Review assesses emerging data indicative of a specific role for the RB tumour suppressor pathway in the response of the haematopoietic system to oxidative stress. This is mediated through signalling pathways that involve DNA damage sensors, forkhead box O (Foxo) transcription factors and p38 mitogen-activated protein kinases and has downstream consequences for cell cycle progression, antioxidant capacity, mitochondrial mass and cellular metabolism.

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Figure 1: The retinoblastoma (RB) pathway in stress responses and cancer.
Figure 2: Oxidative stress responses link the retinoblastoma (RB) pathway and Forkhead box O (Foxo) transcription factors.
Figure 3: Functional interactions of E2f transcription factors with other transcription factors in oxidative stress responses.

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Acknowledgements

The author is grateful to the J. P. McCarthy Foundation, the Aplastic Anaemia and MDS International Foundation and the National Heart Lung & Blood Institute (RO1 HL080262) for funding of work in her laboratory relating to oxidative stress, erythropoiesis and haematopoietic diseases. The author also gratefully acknowledges the experimental skills and intellectual input to work in the laboratory in the related research area by current laboratory members K. Tracy, J. Knabb and D. Glick and by former graduate students in the laboratory B. T. Spike and A. Dirlam.

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  1. Ben May Department for Cancer Research, Committee on Cancer Biology, University of Chicago, 929 East 57th Street, Chicago, 60637, Illinois, USA

    Kay F. Macleod

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DATABASES

National Cancer Institute

bladder cancer

prostate cancer

National Cancer Institute Drug Dictionary

5-fluorouracil

cisplatin

etoposide

mitomycin C

OMIM

ataxia telangiectasia

Nijmegen breakage syndrome

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Glossary

Haematopoietic stem cell

A cell residing at the apex of the cellular hierarchy in the haematopoietic system that gives rise to all other lineages and cell types in the blood system.

Non-cell-autonomous

Effects in tissues that are the consequence of a defect or altered phenotype in a different tissue or cell type.

Vav–Cre

Expression of the Cre recombinase under the control of the Vav promoter. which is restricted in its expression to haemangioblast-derived cell types. Thus Vav–Cre drives deletion of floxed alleles in embryonic and adult haematopoietic stem cells and their progeny, as well as in endothelial cells.

Poly(I)poly(C)

A form of double-stranded RNA that is a potent inducer of interferon and is used to activate the Mx1 promoter driving Cre recombinase expression.

Mx1–Cre

Expression of the Cre recombinase under the control of the silent Mx1 gene promoter: Cre is not expressed unless the transgenic mouse is challenged with agents that induce the interferon response, such as poly(I)poly(C). Expression is high in the haematopoietic system, liver and kidneys and lower in other cell types tested.

N-cadherin

A member of the cadherin family of cell–cell adhesion proteins bearing conserved structural motifs known as 'cadherin repeats'. N-cadherin is highly expressed in mature neurons.

Repopulating capacity

The ability of haematopoietic tissue and cells to regenerate the blood system when transplanted into host animals that have had their bone marrow ablated through exposure to lethal or sublethal doses of ionizing irradiation or to cytotoxic drugs.

Myeloproliferation

Expansion of myeloid elements within the blood system.

Osteoclasts

Myeloid-derived cells within the bone marrow niche that interact with bone matrix and osteoblasts to influence stem cell development.

Antioxidants

Compounds and enzymes that neutralize ROS by accepting electrons from free radicals.

Fanconi anaemia

A cancer susceptibility syndrome in which genetically predisposed individuals are sensitized to DNA crosslinking agents, experience bone marrow failure and anaemia and show varying degrees of developmental abnormalities.

Poly(ADP-ribose)

A polymer generated by and conjugated to target proteins by members of the poly(ADP)-ribose polymerase resulting in increased negative charge and altered activities of modified proteins.

Pentose phosphate pathway

A series of enzymatic reactions in which NADPH is produced in cells by conversion of glucose-6-phsophate to ribulose-5-phosphate.

Fenton reaction

The oxidation of Fe2+ to generate Fe3+ and highly reactive hydroxyl radicals.

Ischaemia

Deprivation or insufficiency of blood supply to tissues associated with hypoxia and nutrient deprivation, frequently with necrotic cell death.

Endosteal surface

The inner surface of bone bordering the bone marrow cavity.

Ki67

Ki67 is a marker of proliferation that may have a role in ribosome biogenesis. Immunohistochemical staining for Ki67 on tumour sections and tissues is commonly used to mark out proliferating cells in situ.

Cyclooxygenase 2

(COX2). An enzyme with both peroxidase and dioxygenase activity involved in synthesis of prostaglandins from arachadonic acid, COX2 is activated by inflammation and upregulated in colorectal, breast and other cancers. COX2 inhibitors are used as anti-inflammatory drugs.

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Macleod, K. The role of the RB tumour suppressor pathway in oxidative stress responses in the haematopoietic system. Nat Rev Cancer 8, 769–781 (2008). https://doi.org/10.1038/nrc2504

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