Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewCyclin D-dependent kinases, INK4 inhibitors and cancer
Introduction
Mammalian cells proliferate, differentiate or die in response to extracellular signals. However, when these cells acquire a malignant phenotype, they lose responsiveness to many of these signals. Indeed, one of the hallmarks of transformed cells is their lack of growth control. Cancer cells either do not require mitogenic stimulation to proliferate or their requirements are by far less stringent than those of normal cells. Likewise, cancer cells are less likely to exit the cell cycle to reach a quiescent state in response to growth inhibitory signals. These phenotypic properties are the result of genetic and/or epigenetic alterations in a variety of molecules and growth regulatory pathways either directly or indirectly involved in cell cycle control. Genetic analysis of human tumors has revealed that some of the molecules most often altered in cancer are those involved in the control of the G1/S transition of the cell cycle, a time when cells become committed to a new round of cell division. In particular, the cyclin-dependent kinase (Cdk)–cyclin D/INK4/retinoblastoma (pRb)/E2F cascade has been found to be altered in more than 80% of human neoplasias, either by mutations within the genes encoding these proteins or in their upstream regulators. In this review, we will focus on the regulation of the Rb family of proteins by the D-cyclin-dependent Cdks, Cdk4 and Cdk6, and the INK4 family of cell cycle inhibitors and how its imbalance contributes to tumor development.
Section snippets
The role of Cdk4 in G1
G1 is the initial phase of the cell cycle when cells must acquire all the necessary information to proceed safely into the next phase, S, when their genetic dowry has to be faithfully duplicated. Cells enter G1 either after completing cytokinesis if they are actively proliferating (M/G1 transition) or from a quiescent state known as G0 if they have previously exited the cycle (G0/G1 transition) (Fig. 1). During these transitions, cells evaluate their extracellular environment to ensure they
Cdk4 regulators: D-type cyclins
D-type cyclins (D1, D2 and D3) are the major downstream targets of extracellular signaling pathways. Mitogenic signals induce D-type cyclin expression, assembly with Cdk4 and Cdk6, nuclear localization and turnover [9]. There is abundant experimental evidence for the implication of D-type cyclins in driving cultured cells through G1 (reviewed in [5], [6], [10], [21]). For instance, blocking D-type cyclins during G1 with specific antibodies prevents cells from entering the S phase [22], [23].
Regulation of Cdk4 activity by INK4 proteins
In 1994, a tumor suppressor gene, designated MTS1 (multiple tumor suppressor 1), was located on human chromosome 9p21 [28]. This gene was previously described as a cell cycle inhibitory protein [29]. Today, this gene is known as P16INK4a and serves as prototype for the INK4 (inhibitors of Cdk4) family of cell cycle inhibitors. Detailed analysis of the 9p21 chromosomal region uncovered the presence of a second tumor suppressor MTS2 [28], also identified independently as a member of the INK4
Function of INK4 proteins in mice
The specific role of each of the four members of the INK4 family of cell cycle inhibitors is being elucidated by genetic approaches, mainly the generation of gene-targeted strains of mice lacking one or various members of this gene family (Table 1). Targeted inactivation of the INK4a locus in the mouse germ line was first reported by Serrano et al. [52]. These investigators deleted exons 2 and 3 since at that time the existence of P19ARF was not known. Mice homozygous for this mutation,
Cooperation between INK4 and Cip/Kip families of cell cycle inhibitors
Crosses between mice defective for individual members of the INK4 and Cip/Kip families of cell cycle inhibitors have revealed a significant level of functional cooperativity (reviewed in [72]) (Table 1). For instance, P18INK4c and P27Kip1 cooperate in tumor suppression in pituitary cells [58]. Whereas in each individual knock out strain pituitary tumors appear after around 10 months, (P18INK4c; P27Kip1) double null animals die from pituitary adenomas by 3–4 months of age [58]. Interestingly,
Cdk4 activity and tumor development
Misregulation of Cdk4/6 activity by either overexpression of D-type cyclins or loss of INK4 proteins almost invariably leads to hyperproliferative defects and eventually to tumor development. Recently, a mouse model has been generated in which the resident Cdk4 kinase has been made resistant to INK4 inhibition by knocking-in a miscoding mutation [18] originally found in patients with familial melanoma [76], [77]. Specifically, this strain, designated Cdk4R24C, expresses normal levels of an
Cdk4 and Cdk6 in human cancer
As indicated above, the Cdk4/6–cyclin D/INK4/Rb pathway is one of the most frequently mutated in human cancers. In this review, we will only consider those mutations that affect either Cdk4 or Cdk6 kinase activity or its regulation. For a more comprehensive review regarding the incidence of mutations in this pathway in human tumors see [79]. Cdk4 is amplified and overexpressed in a wide variety of tumors and tumor cell lines [80], [81], [82]. Some of them, mainly gliomas [83], [84], [85],
The INK4/Cdk4 pathway as a target for cancer therapy
Due to the central role that Cdks play in the control of the cell cycle they are actively being considered as targets for drug discovery efforts. Indeed, the complexity of Cdk regulation offers a number of possible routes for therapeutic intervention. In principle, Cdk activity can be inhibited by a variety of experimental approaches. Some of the more obvious (albeit not always easy to implement) include overexpression of exogenous INK4 or Cip peptidomimetics, antisense technology, blocking
References (128)
Cell
(1994)Cell
(1995)Cell
(1996)- et al.
Curr. Opin. Cell Biol.
(2000) - et al.
FEBS Lett.
(2001) - et al.
Cell
(1995) - et al.
Genes Dev.
(1999) - et al.
Curr. Opin. Genet. Dev.
(2000) - et al.
Mol. Cell
(2000) J. Mol. Biol.
(1999)
Exp. Cell Res.
Curr. Opin. Cell Biol.
Cell
Cell
Biochim. Biophys. Acta
Cell
Cell
Cell
Am. J. Pathol.
Cancer Lett.
Blood
Proc. Natl. Acad. Sci. USA
Science
Science
Nat. Cell Biol.
Genes Dev.
Cancer Res.
EMBO J.
Mol. Cell. Biol.
EMBO J.
Mol. Cell. Biol.
Mol. Biol. Cell
EMBO J.
Nat. Genet.
Mol. Cell. Biol.
Science
J. Cell Sci.
Genes Dev.
Genes Dev.
Genes Dev.
Nature
Nature
Science
Nature
Nature
Genes Dev.
Mol. Cell. Biol.
Mol. Cell. Biol.
Cell
Genes Dev.
Cited by (679)
Palbociclib and Michael-acceptor hybrid compounds as CDK4/6 covalent inhibitors: Improved potency, broad anticancer spectrum and overcoming drug resistance
2023, Bioorganic and Medicinal ChemistryTargeting immune checkpoints for cancer therapy
2023, Treatment Landscape of Targeted Therapies in Oncology: Challenges and OpportunitiesGenetic factors in Cushing disease pathogenesis
2023, Genetic Steroid Disorders: Second EditionPharmacological Targeting of Senescence with Senolytics as a New Therapeutic Strategy for Neurodegeneration
2024, Molecular Pharmacology