Minichromosomal maintenance protein 7 (MCM7) is an essential component of the replication helicase complex (MCM2-7) required for DNA replication. Although this function is highly conserved among eukaryotes, additional functions for the MCM molecules continue to be described. Minichromosomal maintenance protein 7 is a marker for proliferation and is upregulated in a variety of tumors including neuroblastoma, prostate, cervical and hypopharyngeal carcinomas. To further investigate the general role of MCM7 in tumorigenesis, we generated a mouse model with deregulated MCM7 expression targeted to the basal layer of the epidermis using the keratin 14 (K14) promoter (K14.MCM7). When subjected to a two-stage chemical carcinogenesis protocol (dimethylbenz[a]anthracene (DMBA) initiation with 12-ortho-tetradecanoylphorbol-13-acetate promotion), K14.MCM7 mice showed significantly increased incidence and prevalence of tumor development relative to controls. Furthermore, within 40 weeks of treatment over 45% K14.MCM7 mice exhibited tumors that had converted to squamous cell carcinomas versus none in the control group. As predicted from previous skin carcinogenesis studies using DMBA as the initiating agent, Ras mutations where found in more than 90% of tumors isolated from K14.MCM7 mice. Whereas previous studies have shown that MCM7 is useful as a proliferation marker, our data suggest that deregulated MCM7 expression actively contributes to tumor formation, progression and malignant conversion.
The epidermis is sustained by a multipotent stem cell population that gives rise to cells of different fates including those forming hair follicles, interfollicular epidermis and associated glands such as sebaceous glands. The most intriguing evidence comes from using a variety of mouse models with which studies have found the WNT pathway to be involved in regulating stem cell fate decisions. These mouse models have been used to analyze different members of the WNT pathway in the epidermis and altogether suggest that different levels of beta-catenin correlate with the adoption of different epidermal stem cell fates. Recent data specifically analyzing c-Myc, a downstream target of the WNT pathway, has found that c-Myc can divert epidermal stem cells to a sebaceous gland fate at the expense of hair follicles. Also, newly emerging data using gene expression profiling techniques have uncovered a more direct role of c-Myc in stem cell fate determination.
Multipotent stem cells residing in the bulge region of the hair follicle give rise to cells of different fates including those forming hair follicles, interfollicular epidermis, and associated glands. Stem cell fate determination is regulated by genes involved in both proliferation and differentiation, which are tightly regulated processes. Understanding the molecular mechanisms by which proliferation and differentiation are regulated will provide useful insight into treating human diseases caused by the deregulation of these processes. Two genes involved in regulating proliferation and differentiation are c-Myc and p63, both of which have been found to be deregulated/mutated in several human diseases. Accelerating proliferation leads to neoplastic human diseases and deregulated c-Myc has been implicated in a variety of cancers. Evidence indicates that c-Myc also diverts stem cells to an epidermal and sebaceous gland fate at the expense of the hair follicle fate. Therefore, deregulation of c-Myc has the potential to not only accelerate tumorigenesis, but also influence skin tumor phenotype. In addition, the inhibition of differentiation may also predispose to the development of skin cancer. Recent evidence suggests that the transcription factor p63, is not only responsible for the initiation of an epithelial stratification program during development, but also the maintenance of the proliferative potential of basal keratinocytes in mature epidermis. Mutations in the p63 gene have been shown to cause ectodermal dysplasias and deregulated expression of p63 has been observed in squamous cell carcinomas. In this review, we will discuss recent data implicating a role for both c-Myc and p63 in human skin diseases.
Nonmelanoma skin cancers (NMSCs) consist of a variety of tumor types including basal cell carcinoma, squamous cell carcinoma, a variety of hair follicle tumors, and sebaceous gland tumors. Genetic alterations that alter the fate of multipotent stem cells are believed to influence NMSC phenotype. We previously generated a transgenic mouse line which constitutively expressed c-myc under the control of the K14 promoter (K14.MYC2). These mice exhibited an increase in size and number of sebaceous glands, suggesting that c-myc diverted multipotential stem cells to a sebaceous lineage. Our goal in the current study was to determine if alterations in the commitment of multipotent stem cells to different cell fates would influence tumor phenotype. To this end, we exposed K14.MYC2 mice to a chemical carcinogenesis protocol and discovered that these mice were predisposed to develop sebaceous adenomas. Our data demonstrate that genetic alterations that alter the fate of multipotent stem cells during embryonic development can markedly influence the phenotype of NMSC that develop following exposure to carcinogens.
unveiled a new 7.5 million dollar program, NSF Graduate Teaching Fellows in K-12 Education (GK-12), to partner graduate students in the sciences with high school science teachers "... injecting new energy into ... K-12 positively influencing higher education-all while satiating a desperate hunger for mutual responsibility between all levels of science and mathematics education" (NSF PR 99-12; www.nsf.gov). In 2001, the program was expanded due to the positive responses from both higher education institutions and K-12 schools (NSF PR 01-27; vwww.nsf. ov). The program's design was to allow graduate fellows to serve as content advisors for teachers in science and mathematics; while providing improved communication, teaching, and community outreach skills for the graduate fellows. The GK-12 program ultimately will foster a strong, long lasting partnership between K-12 schools and higher-education institutions (http://www. ns. gov/home/crssprgm/gk 12/).
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