Deregulated expression of c-Myc depletes epidermal stem cells

Waikel, Rebekah L.; Kawachi, Yasuhiro; Waikel, Patricia A.; Wang, Xiaojing; Roop, Dennis R.

doi:10.1038/88889

Cited by 293 publications

(333 citation statements)

References 23 publications

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“…M2SMO samples did not contain detectable levels of Shh mRNA, arguing that the appearance of sebocytes in transgenic skin was not the result of up-regulated Shh expression. In light of recent studies documenting enhanced sebocyte development in mice expressing MYC in skin, 36,37 it is noteworthy that c-Myc expression appeared to be up-regulated in volar skin of M2SMO mice, compared to controls.…”

Section: Resultsmentioning

confidence: 90%

“…The potential influence of cross-talk involving Hedgehog and Wnt 49 or BMP 50 pathways will also need to be examined. In addition, it will be important to explore the relationship between the Hedgehog pathway and other molecules implicated in sebocyte development, including c-Myc, 36,37 PPAR␥, 51,52 and COX-2. 53 Hair follicles and sebaceous glands both undergo cyclic changes after birth, 54 and Shh plays a major role in regulating proliferation of follicle epithelium during times of active growth.…”

Section: Discussionmentioning

confidence: 99%

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Hedgehog Signaling Regulates Sebaceous Gland Development

Allen

Grachtchouk

Sheng

et al. 2003

The American Journal of Pathology

115

104

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Epithelial progenitor cells in skin give rise to multiple lineages, comprising the hair follicle, an associated sebaceous gland, and overlying epidermis; however, the signals that regulate sebocyte development are poorly understood. We tested the potential involvement of the Hedgehog pathway in sebaceous gland development using transgenes designed to either block or stimulate Hedgehog signaling in cutaneous keratinocytes in vivo. Whereas inhibition of the Hedgehog pathway selectively suppressed sebocyte development, Hedgehog pathway activation led to a striking increase both in size and number of sebaceous glands. Remarkably, ectopic Hedgehog signaling also triggered the formation of sebaceous glands from footpad epidermis, in regions normally devoid of hair follicles and associated structures. These ectopic sebaceous glands expressed molecular markers of sebocyte differentiation and were functional, secreting their contents directly onto the skin's surface instead of into a hair canal. The Hedgehog pathway thus plays a key role in sebocyte cell fate decisions and is a potential target for treatment of skin disorders linked to abnormal sebaceous gland function, such as acne.

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Section: Resultsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Hedgehog Signaling Regulates Sebaceous Gland Development

Allen

Grachtchouk

Sheng

et al. 2003

The American Journal of Pathology

115

104

View full text Add to dashboard Cite

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“…31 Interestingly, ectopic expression of MYC in the basal layer of the murine epidermis causes depletion of stem cells and increased differentiation. 39,40 Furthermore, this exit from the stem cell compartment has been linked to repression of adhesion genes and the disruption of critical interactions between stem cells and their specified microenvironment or "niche." 41,42 Most notably, repression of these genes has already been shown to depend on association with MIZ1.…”

Section: Discussionmentioning

confidence: 99%

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

et al. 2016

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Apoptosis caused by deregulated MYC expression is a prototype example of intrinsic tumor suppression. However, it is still unclear how supraphysiological MYC expression levels engage specific sets of target genes to promote apoptosis. Recently, we demonstrated that repression of SRF target genes by MYC/MIZ1 complexes limits AKT-dependent survival signaling and contributes to apoptosis induction. Here we report that supraphysiological levels of MYC repress gene sets that include markers of basal-like breast cancer cells, but not luminal cancer cells, in a MIZ1-dependent manner. Furthermore, repressed genes are part of a conserved gene signature characterizing the basal subpopulation of both murine and human mammary gland. These repressed genes play a role in epithelium and mammary gland development and overlap with genes mediating cell adhesion and extracellular matrix organization. Strikingly, acute activation of oncogenic MYC in basal mammary epithelial cells is sufficient to induce luminal cell identity markers. We propose that supraphysiological MYC expression impacts on mammary epithelial cell identity by repressing lineage-specific target genes. Such abrupt cell identity switch could interfere with adhesiondependent survival signaling and thus promote apoptosis in pre-malignant epithelial tissue.

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“…Recent data have underlined the important role of MYC in the differentiation of skin epithelium (Pelengaris et al, 2002;Alonso and Fuchs, 2003). Through the depletion of integrin b (Waikel et al, 2001), MYC was found to act selectively on epidermal stem cells (Gandarillas and Watt, 1997), driving them into the transit amplification compartment and stimulating differentiation into interfollicular epidermis and sebocytes (Frye et al, 2003). In an experimental model, MYC activation was sufficient to induce a neoplastic phenotype in the skin (Pelengaris et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

et al. 2006

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To determine whether integration of human papillomavirus (HPV) DNA sequences could lead to the deregulation of genes implied in oncogenesis, we analysed the HPV integration sites in a series of nine cell lines derived from invasive genital carcinomas. Using in situ hybridization, HPV16 or 18 sequences were found at chromosome band 8q24, the localization of MYC, in IC1, IC2, IC3, IC6 and CAC-1 cells and at other sites in IC4, IC5, IC7 and IC8 cells. We then localized viral sequences at the molecular level and searched for alterations of MYC structure and expression in these cells. MYC genomic status and viral integration sites were also analysed in primary tumors from which IC1, IC2, IC3 and IC6 cells were derived. In IC1, IC2 and CAC-1 cells, HPV DNA was located within 58 kb of MYC, downstream, upstream, or within MYC. In IC3 and IC6 cells, HPV DNA was located 400-500 kb upstream of MYC. Amplification studies showed that, in IC1, IC2 and IC3, viral and MYC sequences were coamplified in an amplicon between less than 50 and 800 kb in size. MYC amplification was also observed in primary tumors, indicating that this genetic alteration, together with viral insertion at the MYC locus, had already taken place in vivo. MYC was not amplified in the other cell lines. MYC mRNA and protein overexpression was observed in the five cell lines in which the HPV DNA was inserted close to the MYC locus, but in none of the lines where the insertion had occurred at other sites. MYC activation, triggered by the insertion of HPV DNA sequences, can be an important genetic event in cervical oncogenesis.

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Deregulated expression of c-Myc depletes epidermal stem cells

Cited by 293 publications

References 23 publications

Hedgehog Signaling Regulates Sebaceous Gland Development

Hedgehog Signaling Regulates Sebaceous Gland Development

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

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