HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation

Authors

  • László G. Kömüves,

    1. Department of Dermatology, VA Medical Center and University of California, San Francisco, San Francisco, California
    Current affiliation:
    1. Cor Therapeutics, South San Francisco, CA.
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  • Elias Michael,

    1. Department of Dermatology, VA Medical Center and University of California, San Francisco, San Francisco, California
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  • Jeffrey M. Arbeit,

    1. Department of Surgery, University of California San Francisco, San Francisco, California
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  • Xiao-Kui Ma,

    1. Department of Dermatology, VA Medical Center and University of California, San Francisco, San Francisco, California
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  • Angela Kwong,

    1. Department of Dermatology, VA Medical Center and University of California, San Francisco, San Francisco, California
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  • Eric Stelnicki,

    1. Department of Dermatology, VA Medical Center and University of California, San Francisco, San Francisco, California
    Current affiliation:
    1. Department of Surgery, Cleveland Clinic Florida, Fort Lauderdale, FL.
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  • Sophia Rozenfeld,

    1. Department of Dermatology, VA Medical Center and University of California, San Francisco, San Francisco, California
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  • M. Morimune,

    1. Department of Dermatology, VA Medical Center and University of California, San Francisco, San Francisco, California
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  • Qian-Chun Yu,

    1. Department of Dermatology, VA Medical Center and University of California, San Francisco, San Francisco, California
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  • Corey Largman

    Corresponding author
    1. Department of Dermatology, VA Medical Center and University of California, San Francisco, San Francisco, California
    2. Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco, San Francisco, California
    • (151H), VA Medical Center, 4150 Clement Street, San Francisco, CA 94121
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  • This article is a US Government work and, as such, is in the public domain in the United States of America.

Abstract

The HOX homeodomain proteins are fundamental regulators of organ and tissue development, where they are thought to function as transcription factors, and HOX gene expression has been associated with numerous types of cancers. Previous studies have demonstrated that enforced expression of the HOXB4 protein transforms cultured fibroblasts and leads to a selective expansion of the hematopoietic stem cell pool, suggesting that this protein might play a role in cellular proliferation. In support of this concept, we now show that enforced expression of HOXB4 in human neonatal keratinocytes results in increased cellular proliferation and colony formation as well as decreased expression of the alpha-2-integrin and CD44 cell surface adhesion molecules. We previously have reported HOXB4 gene expression in the basal and suprabasal layers of developing human skin and now show extensive HOXB4 mRNA in psoriatic skin and basal cell carcinoma. In fetal human skin HOXB4 protein expression was both nuclear and cytoplasmic within epidermal basal cells and in hair follicle inner and outer root sheath cells, whereas strong nuclear signals were observed in the bulge region. In adult skin, HOXB4 protein expression was both nuclear and cytoplasmic, but was predominantly localized to the intermediate and differentiated cell layers. In contrast to the striking gradient patterns of HOX gene and protein expression previously described in developing spinal cord and limb, HOXB4 protein was uniformly detected in all regions of the fetal and adult skin. Although little HOXB4 signal localized to proliferative cell layers, as marked by proliferating cell nuclear antigen (PCNA) staining, in normal adult epidermis, nuclear HOXB4 protein expression substantially overlapped with PCNA-positive cell in a series of samples of hyperproliferative skin. Taken together, these data suggest that nuclear HOXB4 protein may play a role in the regulation of cellular proliferation/adhesion in developing fetal human epidermis and in hyperproliferation conditions, including cancers, in adult epidermis. Published 2002 Wiley-Liss, Inc.

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