A Mitosis Block Links Active Cell Cycle with Human Epidermal Differentiation and Results in Endoreplication

Abstract

How human self-renewal tissues co-ordinate proliferation with differentiation is unclear. Human epidermis undergoes continuous cell growth and differentiation and is permanently exposed to mutagenic hazard. Keratinocytes are thought to arrest cell growth and cell cycle prior to terminal differentiation. However, a growing body of evidence does not satisfy this model. For instance, it does not explain how skin maintains tissue structure in hyperproliferative benign lesions. We have developed and applied novel cell cycle techniques to human skin in situ and determined the dynamics of key cell cycle regulators of DNA replication or mitosis, such as cyclins E, A and B, or members of the anaphase promoting complex pathway: cdc14A, Ndc80/Hec1 and Aurora kinase B. The results show that actively cycling keratinocytes initiate terminal differentiation, arrest in mitosis, continue DNA replication in a special G2/M state, and become polyploid by mitotic slippage. They unambiguously demonstrate that cell cycle progression coexists with terminal differentiation, thus explaining how differentiating cells increase in size. Epidermal differentiating cells arrest in mitosis and a genotoxic-induced mitosis block rapidly pushes epidermal basal cells into differentiation and polyploidy. These observations unravel a novel mitosis-differentiation link that provides new insight into skin homeostasis and cancer. It might constitute a self-defence mechanism against oncogenic alterations such as Myc deregulation.

Cyclin E drives human keratinocyte growth into differentiation

“…11 Mitosis kinases Aurora B or Polo-like kinase 1 (Plk1), which are involved in chromosome segregation, participate in the mitotic spindle checkpoint 32,33 and some of their inhibitors are being tested in cancer clinical trials. 34 To explore whether the keratinocyte mitotic checkpoints are involved in the signal to differentiation, we inhibited these molecules by specific chemical inhibitors.…”

“…We have previously shown that postmitotic keratinocytes continue DNA synthesis and become polyploid during differentiation in vitro 9 and in vivo, 10,11 and that the process of endoreplication is stimulated by MYC. As for MYC, other molecules involved in cell cycle progression caused epidermal hyperplasia, but were not able to disrupt differentiation (for example, E2F, Cyclin D1, MDM2, cdk2, cdk4; references in Zanet et al 11 ).…”

“…As for MYC, other molecules involved in cell cycle progression caused epidermal hyperplasia, but were not able to disrupt differentiation (for example, E2F, Cyclin D1, MDM2, cdk2, cdk4; references in Zanet et al 11 ). Cyclin-dependent kinases cdk2 and cdk1 are key regulators of S-phase and mitosis, respectively.…”

A new level of spindle assembly checkpoint inactivation that functions without mitotic spindles

“…This might help explain why, following exit from mitotic SAC arrest, some cell types undergo cell death, while others can continue to cycle or potentially differentiate into nondividing polyploid cells. [2][3][4]9 In the case of A. nidulans, which normally maintains multiple nuclei within a syncytium, the failed mitosis which occurs during SIME is tolerated. This is because the genome of syncytial cells normally doubles each cell cycle and this still occurs when mitosis fails and cells undergo SIME.…”

p27Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

“…Somatic polyploidy has several advantages for the affected cells including a better response to metabolic and/or genotoxic stress and a lower sensibility to apoptotic stimuli. 10,11,20,21 In mammals and higher vertebrates different cell types have been shown to be polyploid, including trophoblast giant cells, 10,11,,22 hepatocytes, 23,24 megakaryocytes, 25 keratinocytes, 26 and vascular smooth cells. 27 Endoreplication represents a major mechanism leading to developmental programmed somatic polyploidy.…”