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  • Review Article
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CDKS and CKIS: Molecular targets for tissue remodelling

Nature Reviews Drug Discovery volume 1, pages 587–598 (2002)Cite this article

Key Points

  • Effective tissue remodelling is essential to the survival of adult organs. Tissue remodelling is a regulated balance between pro- and anti-proliferative molecules. The cyclin-dependent kinases (CDKs) and the CDK inhibitors (CKIs) are a new class of therapeutic agents that target tissue remodelling in many organ systems. Understanding the circuitry of cyclin–CDK–CKI interactions in normal physiology and disease pathophysiology allows the rational design of new molecular therapies that have broad applicability to tissue remodelling. Conceptually, two approaches have been taken: targeting the CDKs through the design of inhibitors, such as the CDK-specific ATP antagonists; or targeting the tumour-suppressor proteins, or CKIs, INK4A (inhibitor of CDK4, polypeptide A), CIP1 (CDK-inhibitory protein 1) and KIP1 (kinase-inhibitory protein 1).

  • Molecular and biochemical studies have defined the complex interactions between the cyclins, CDKs and the CKIs. Mitogen-stimulated progression through the G1 phase of the cell cycle and initiation of DNA replication in S phase are coordinated by the CDKs, the activities of which are regulated by CKIs. The CDKs are holoenzyme complexes that contain cyclin-regulatory and CDK-catalytic subunits. Two families or enzymes mediate restriction-point control — the cyclin D- and cyclin E-dependent kinases. The CKIs are classified into two families on the basis of their structures and CDK targets: the CIP/KIP proteins, which act broadly on the cyclin D-, cyclin E- and cyclin A-dependent kinases, including CIP1, KIP1 and KIP2; and the INK4A proteins — INK4A, INK4B, INK4C and INK4D.

  • Blood vessels undergo a reparative process after vascular injury that is characterized by vascular-smooth-muscle-cell proliferation and inflammation, which leads to occlusive vascular lesions. Molecular-genetic studies provide evidence that KIP1 and CIP1 suppress excessive cell proliferation, apoptosis and matrix-protein production in arteries. Therapeutic strategies focus on upregulation of KIP1 and other CKIs within vascular lesions through drug-eluting stents.

  • The CIP/KIP proteins have distinct roles in subcompartments of the bone marrow to preserve proliferative capacity and robust replacement under stress conditions. CIP1 functions as a molecular switch to regulate the entry of stem cells into the cell cycle, and overexpression of CIP1 might be useful in preparative regimens for bone-marrow transplantation and stem-cell therapies. KIP1 controls progenitor proliferation and pool size, making it an attractive molecular target for manipulating stem-cell pool size ex vivo.

  • Cell proliferation and extracellular-matrix production are hallmarks of inflammatory diseases in many organ systems, including glomerulonephritis, dermatitis, arthritis, cirrhosis and atherosclerosis. The role of the CIP/KIP proteins in arresting cell proliferation and reducing inflammatory injury raises interesting possibilities for molecular therapies. Early clinical studies are examining the role of CKIs, as well as molecules that upregulate the expression of KIP1 or prevent its degradation, and these look promising for the treatment of glomerulonephritis and peripheral tolerance.

  • Most human cancers sustain mutations that alter the function of the retinoblastoma tumour-suppressor protein (RB) or the p53 transcription factor by direct mutation of gene sequences or by targeting genes that act epistatically to prevent their normal function. Functional disruption of RB or INK4A, or overexpression of cyclin D1 and CDK4, occur in many cancers, indicating that disabling the RB pathway might be essential for tumorigenesis. Promising approaches to treating dysregulation of RB and p53 pathways include CDK-specific ATPase antagonists, protein and peptide inhibitors of CDKs, and possibly the genetic manipulation of CIP/KIP proteins. CKIs are also being tested for prevention of chemotherapy-induced alopecia. The most promising approaches for molecular therapies of human malignancies are the CKIs.

Abstract

Effective tissue remodelling is essential to the survival of adult organs. Many of the signalling pathways that control these cellular decisions are regulated by nuclear interactions of cell-cycle proteins. Molecules that target cyclin-dependent kinases (CDKs) or CDK inhibitors (CKIs) represent a new class of therapeutic agents that influence tissue remodelling in several organ systems. An understanding of their cell-specific functions is leading to the development of exciting and bold approaches to the treatment cancer, cardiovascular disease and other diseases.

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Figure 1: The CKIs and systemic diseases.
Figure 2: Cell-cycle pathways.
Figure 3: CKI regulation in normal physiology.
Figure 4: CKI regulation in disease pathophysiology.
Figure 5: CKIs are molecular targets to treat vascular proliferative diseases.
Figure 6: CIP1 and KIP1 distinctly affect haematopoiesis.

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Authors and Affiliations

  1. Cardiovascular Branch, National Heart, Lung and Blood Institute/National Institutes of Health, Building 10/8C103, 10 Center Drive, Bethesda, 20892, Maryland, USA

    Elizabeth G. Nabel

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DATABASES

Cancer.gov

breast cancer

colon cancer

head and neck cancer

leukaemia

lung cancer

lymphoma

ovarian cancer

prostate tumours

LocusLink

AKT

ARF

calcineurin

CD34

CDK2

CDK4

CDK6

CDKN2A

CIP1

cyclin A

cyclin D

cyclin E

FKBP12

HDM2

IL-2

INK4B

INK4C

INK4D

JAB1

c-JUN

KIP1

KIP2

KIS

MAPKK1

MAPKK2

Mdm2

p53

PCNA

PI3K

p7056K

RB

SP1

TGF-β

TOR

Medscape DrugInfo

aspirin

paclitaxel

FURTHER INFORMATION

FDA

Glossary

CYCLIN-DEPENDENT KINASES

(CDKs). Holoenzymes that contain regulatory (cyclin) and catalytic (CDK) subunits. Two families of enzymes — the cyclin D- and cyclin E-dependent kinases — regulate the G1-to-S-phase transition.

CDK INHIBITORS

(CKIs) There are two families of CDK inhibitors, which are assigned according to their structure and CDK targets. The INK4 proteins specifically inhibit the catalytic subunits of CDK4 and CDK6. The CIP/KIP family affects the activities of cyclin D-, cyclin E- and cyclin A-dependent kinases.

TUMOUR-SUPPRESSOR PROTEIN

A protein that suppresses the formation of tumours or, alternatively, a protein that promotes carcinogenesis when inactivated.

CIP/KIP FAMILY

A family of genes that includes CIP1, KIP1 and KIP2. CIP stands for CDK-inhibitory protein. KIP stands for kinase-inhibitory protein.

INK4 FAMILY

The inhibitor-of-CDK4 family. A family of genes that encode an inhibitor of CDK4, and which are designated in the order of discovery: INK4A, INK4B, INK4C and INK4D.

RETINOBLASTOMA TUMOUR-SUPPRESSOR PROTEIN

(RB). The retinoblastoma tumour-suppressor protein limits cell proliferation by preventing entry into the S phase of the cell cycle. It does this, in part, by blocking E2F transcription factors from activating genes that are needed for DNA replication.

E2F TRANSCRIPTION FACTOR

A heterodimeric transcription factor that is composed of an E2F subunit and either DP1 or DP2.

HAEMATOPOIETIC PROGENITOR CELLS

These cells give rise to more mature cell types and might or might not be self-renewing.

RESTENOSIS

A recurrence of clinical symptoms after percutaneous transluminal coronary angioplasty (PTCA). The pathology results from elastic recoil of the vessel, platelet thrombosis, vascular-smooth-muscle-cell hyperplasia and vascular remodelling.

RESTENOSIS RATE

The percentage of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) who develop restenosis.

IMMUNOPHILIN

A cytosolic protein that binds to immunosuppressive drugs.

HAEMATOPOIETIC STEM CELLS

These self-renewing cells give rise to mature, circulating red and white blood cells.

GLOMERULONEPHRITIS

A group of diseases in the kidney that are caused by inflammation and cell proliferation, which results in gradual, progressive destruction of the internal kidney structures or glomeruli.

HAPLOINSUFFICIENCY

A state in which loss of only one of two alleles of a gene disables its function.

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Nabel, E. CDKS and CKIS: Molecular targets for tissue remodelling. Nat Rev Drug Discov 1, 587–598 (2002). https://doi.org/10.1038/nrd869

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