Elsevier

Drug Resistance Updates

Volume 10, Issues 1–2, February–April 2007, Pages 13-29
Drug Resistance Updates

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

https://doi.org/10.1016/j.drup.2007.01.003Get rights and content

Abstract

The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16Ink4a, p15Ink4b, p18Ink4c, p19Ink4d), and the Cip1/Waf1/Kip1-2-family (p21Cip1/Waf1, p27Kip1, p57Kip2) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-XL Mcl-1L; Bax, Bok/Mtd, Bak, and Bcl-XS; Bad, Bid, BimEL, Bmf, Mcl-1S) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G1-S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.

Section snippets

General introduction: linking cell cycle, cell survival and cell death

Molecular linkages between cell death, cell survival, and cell cycle have become an object of intense research in recent years (Table 1). The standard eukaryotic cell cycle is divided into four non-overlapping phases, with DNA synthesis and mitosis occurring during S phase and M phase, respectively. These landmark events are separated by G1 and G2 gap phases during which mRNAs and proteins accumulate continuously. In G1 phase the cell is preparing for DNA synthesis, the cell is growing and the

PI3-Kinase/Akt pathway controls cell survival, cell cycle and apoptosis

The Phosphatidylinositol 3′-kinase (PI3-K)/Akt signaling pathway is regarded as one of the key pro-survival pathways within the cell. It is activated by many types of cellular stimuli – but also by toxic insults – and regulates fundamental cellular functions such as proliferation, growth, transcription, translation, cell cycle and also apoptosis (Cantley, 2002, Vanhaesebroeck and Alessi, 2000). Notably, it has been shown that PI3-K/Akt signaling is frequently disrupted in human cancers and

Cyclins and cyclin-dependent kinases

We have delineated in the introduction the role of cyclins, CDKs and their inhibitors for cell cycle progression. We will now discuss in greater detail the interactions of cyclins, CDKs and their natural and pharmacologic inhibitors, focusing on their role in cell cycle progression, apoptosis induction and cancerogenesis.

Role of cyclin-depedent kinases in the regulation of cell cycle and apoptosis

CDKs are a family of hetero-dimeric serine/threonine kinases that are essential for the progression of the cell cycle at every phase transition of the division process. In addition, they have distinct roles in regulating transcription and neuronal function. CDKs need to be complexed with their activating partners, cyclins, to exert their role on cell proliferation. CDKs, associated cyclins and CDK inhibitors act in a coordinated manner to achieve cellular homeostasis. Dysregulation of the CDKs

Effect of CDK inhibitors during cell cycle and apoptosis

Cyclin-dependent kinases exert their cell cycle-regulatory functions by phosphorylating an array of substrates. The activity of these kinases can be limited by specific, endogenous or exogenous, cyclin dependent kinase inhibitors (CDKIs). There are two major families of endogenous CDKIs. The first family includes the INK4 (inhibitors of CDK4) proteins, which bind and inhibit CDK4 and CDK6 specifically during the G1 phase. There are four such proteins: p16Ink 4a, p15Ink 4b, p18Ink 4c, p19Ink 4d.

Role of p53, E2F and Retinoblastoma protein in the control of apoptosis and cell cycle

Many reviews discuss the role of p53, Rb and E2F in the regulation of cell proliferation and cell death; thus this paragraph aims only to highlight the most important facts about these proteins (Finlan and Hupp, 2005, Yu, 2006). It is considered that tumor suppressor genes have appeared during evolution probably to protect multicellular organisms from uncontrolled cellular division caused by arising mutations. This concept is supported by the fact that the corresponding proteins or pathways are

Dual role of Myc family members in regulating cell cycle and apoptosis

Twenty-five years have passed since c-Myc was discovered as the cellular homologue of the transduced oncogene of several avian retroviruses (Sheiness et al., 1978, Vennstrom et al., 1982). The gene encodes a transcription factor of the HLH/leucine zipper family of proteins that activates transcription as part of a heteromeric complex with a protein termed Max. Altogether, Myc family members function as regulators of gene transcription by heterodimerizing with Max through a network of

The dual role of Bcl2-family members in cell cycle regulation and apoptosis

Bcl2 family members are present in cells of all multi-cellular organisms and they play the key role in the regulation of mitochondria/apoptosome-dependent apoptosis. Proteins of the Bcl2 family can be further classified as either pro-apoptotic or anti-apoptotic and are characterized by distinct, evolutionarily conserved Bcl2 homology domains of which there are four (BH1-4). There are two types of pro-apoptotic Bcl2-family members. The majority of the pro-apoptotic Bcl2-family members are known

Conclusion and future directions

As our understanding of cancer biology increases, so do the chances for the development of more effective and selective, targeted cancer therapies (Broxterman and Georgopapadakou, 2005). So far, much success has been achieved in the development of therapies that target malignancies associated with the overexpression of BCR-Abl (i.e. Gleevec), or a broad array of tumors that hyperactivated the EGFR/Her/Neu pathway (Booy et al., 2006, Brown and Gibson, 2005, Johnston et al., 2006, Krzemieniecki

Acknowledgements

M.L. thankfully acknowledges the support by the CFI-Canada Research Chair program, PCRFC-CCMF-, MMSF, MHRC, and CIHR-foundation-financed programs. S.M. thankfully acknowledges the support by the MHRC-, CCMF-and by Univ. Manitoba funded fellowships. S.P., E.W., and K.W. thankfully acknowledge the support by CIHR-training fellowship. A.Z. S.P. and M.E. acknowledge the generous by CCMF-funded fellowships.

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