Deletion of delta-opioid receptor in mice alters skin differentiation and delays wound healing.

In addition to their well-known antinociceptive action, opioids can modulate non-neuronal functions, such as immune activity and physiology of different cell types. Several findings suggest that the delta-opioid receptor (DOR) and its endogenous ligands (enkephalins) are important players in cell differentiation and proliferation. Here we show the expression of DOR in mouse skin and human skin cultured fibroblasts and keratinocytes using RT-PCR. In DOR knock-out (KO) mice, a phenotype of thinner epidermis and higher expression of cell differentiation marker cytokeratin 10 (CK 10) were observed compared with wild type (WT). Using a burn wound model, significant wound healing delay (about 2 days) and severe epidermal hypertrophy were shown at the wound margin of DOR KO mice. This wound healing delay was further investigated by immunohistochemistry using markers for proliferation, differentiation, re-epithelialization, and dermal repair (CK 6, CK 10, and collagen IV). The levels of all these markers were increased in wounds of KO mice compared with WT. During the wound healing, the epidermal thickness in KO mice augments faster and exceeds that of the WT by day 3. These results suggest an essential role of DOR in skin differentiation, proliferation, and migration, factors that are important for wound healing.

Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer.

Downmodulation or loss-of-function mutations of the gene encoding NOTCH1 are associated with dysfunctional squamous cell differentiation and development of squamous cell carcinoma (SCC) in skin and internal organs. While NOTCH1 receptor activation has been well characterized, little is known about how NOTCH1 gene transcription is regulated. Using bioinformatics and functional screening approaches, we identified several regulators of the NOTCH1 gene in keratinocytes, with the transcription factors DLX5 and EGR3 and estrogen receptor β (ERβ) directly controlling its expression in differentiation. DLX5 and ERG3 are required for RNA polymerase II (PolII) recruitment to the NOTCH1 locus, while ERβ controls NOTCH1 transcription through RNA PolII pause release. Expression of several identified NOTCH1 regulators, including ERβ, is frequently compromised in skin, head and neck, and lung SCCs and SCC-derived cell lines. Furthermore, a keratinocyte ERβ-dependent program of gene expression is subverted in SCCs from various body sites, and there are consistent differences in mutation and gene-expression signatures of head and neck and lung SCCs in female versus male patients. Experimentally increased ERβ expression or treatment with ERβ agonists inhibited proliferation of SCC cells and promoted NOTCH1 expression and squamous differentiation both in vitro and in mouse xenotransplants. Our data identify a link between transcriptional control of NOTCH1 expression and the estrogen response in keratinocytes, with implications for differentiation therapy of squamous cancer.

Iowa Motor Fuel Tax Monthly Reports, December 2001

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.

Iowa Motor Fuel Tax Monthly Reports, November 2001

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.

Iowa Motor Fuel Tax Monthly Reports, October 2001

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.

Iowa Motor Fuel Tax Monthly Reports, September 2001

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.

Iowa Motor Fuel Tax Monthly Reports, August 2001

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.

Iowa Motor Fuel Tax Monthly Reports, July 2001

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.

Iowa Motor Fuel Tax Monthly Reports, January 2002

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.

Iowa Motor Fuel Tax Monthly Reports, February 2002

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.

Iowa Motor Fuel Tax Monthly Reports, March 2002

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.

Iowa Motor Fuel Tax Monthly Reports, April 2002

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.

Iowa Motor Fuel Tax Monthly Reports, May 2002

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.

Iowa Motor Fuel Tax Monthly Reports, June 2002

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.

Iowa Motor Fuel Tax Monthly Reports, July 2002

The monthly fuel tax report from Iowa Department of Transportation to the Iowa Department of Revenue and Finance.