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Deregulation of the cell cycle in cancer
1Division of Cancer Biology Research, Sunnybrook and Women's College Health Science Centre, Toronto, Ontario, Canada.
Abstract:
Mitogenic and growth-inhibitory signals influence cell-cycle progression through their action on a family of cyclin-dependent kinases (cdks). The activity of cdk complexes is regulated in part by the association of a cyclin partner that acts as a positive effector and by two families of cdk inhibitors, the kinase inhibitor proteins (KIP) and the inhibitors of cdk4 (INK4), which act as negative effectors. In human malignancies, increased expression of cyclins is frequently observed. Cyclin D1 and E are frequently overexpressed in breast cancers, and cyclin E overexpression has been correlated with a poor prognostic outcome. The abrogated expression or the acquisition of mutations that render cdk inhibitors functionally inactive have similarly been found in human malignancies. The p16 gene is frequently deleted or mutated in cancers. Although normal epithelial cells express high levels of p27 protein, reduced levels of p27 have been observed in several human cancers, and this has been consistently correlated with a poor prognostic outcome. In this review, we will provide a brief overview of the cell cycle regulators and then discuss their deregulation in cancers.
Insights
Cell cycle regulators like cyclins and cyclin-dependent kinases (cdks) are crucial for cell growth. Deregulation of these proteins, including increased cyclin expression and decreased cyclin-dependent kinase inhibitor activity, is common in human cancers.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Cell cycle progression is tightly regulated by cyclin-dependent kinases (cdks) and their regulatory partners, cyclins and cyclin-dependent kinase inhibitors (CKIs).
- CKIs are broadly classified into two families: kinase inhibitor proteins (KIPs) and inhibitors of cdk4 (INK4).
- Dysregulation of these cell cycle regulators is a hallmark of cancer development.
Purpose of the Study:
- To provide an overview of key cell cycle regulators.
- To discuss the specific roles of cyclins and CKIs in cell cycle control.
- To examine the mechanisms of deregulation of these proteins in human malignancies.
Main Methods:
- Literature review of cell cycle regulation.
- Analysis of studies on cyclin and CKI expression in various cancers.
- Review of genetic alterations affecting cell cycle regulator genes.
Main Results:
- Overexpression of cyclins, such as Cyclin D1 and Cyclin E, is frequently observed in human cancers, particularly breast cancer.
- Cyclin E overexpression is associated with a poor prognostic outcome.
- Inactivation of CKIs, through gene deletion (e.g., p16) or mutation, and reduced p27 protein levels are common in malignancies and correlate with poor prognosis.
Conclusions:
- Aberrant expression and function of cell cycle regulators are critical events in oncogenesis.
- Understanding the deregulation of cyclins and CKIs offers insights into cancer development and progression.
- Targeting cell cycle pathways presents potential therapeutic strategies for cancer treatment.