HIF-1α controls keratinocyte proliferation by up-regulating p21(WAF1/Cip1)

Cho, Young Suk; Bae, Jae Moon; Chun, Yang Sook; Chung, Jin Ho; Jeon, Yoon Kyung; Kim, In San; Kim, Myung Suk; Park, Jong-Wan

doi:10.1016/j.bbamcr.2007.11.017

Cited by 49 publications

(53 citation statements)

References 34 publications

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“…This is most probably due to the well-recognized negative feedback regulation by Smad7 (Ten Dijke et al, 2002), which was detected in the gene expression array. Furthermore, p21CIP expression in keratinocytes in vitro was reported to be strongly upregulated in response to increasing cell density (Cho et al, 2008). Due to the severe growth defect of N-WASP keratinocytes in vitro, the cell density for control and mutant keratinocytes was rather different throughout the experiments and the higher density of control cells could have increased their p21CIP expression.…”

Section: Differential Keratinocyte Gene Expression In the Absence Of mentioning

confidence: 99%

N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGFβ pathways

Lefever

Pedersen

Basse

et al. 2010

Journal of Cell Science

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N-WASP is a cytoplasmic molecule mediating Arp2/3 nucleated actin polymerization. Mice with a keratinocyte-specific deletion of the gene encoding N-WASP showed normal interfollicular epidermis, but delayed hair-follicle morphogenesis and abnormal hair-follicle cycling, associated with cyclic alopecia and prolonged catagen and telogen phases. The delayed anagen onset correlated with an increased expression of the cell-cycle inhibitor p21CIP, and increased activity of the TGFβ pathway, a known inducer of p21CIP expression. Primary N-WASP-null keratinocytes showed reduced growth compared with control cells and enhanced expression of the gene encoding the cell-cycle inhibitor p15INK4B, a TGFβ target gene. Inhibition of TGFβ signaling blocked overexpression of p15INK4B and restored proliferation of N-WASP-deficient keratinocytes in vitro. However, induction of N-WASP gene deletion in vitro did not result in obvious changes in TGFβ signaling or growth of keratinocytes, indicating that the in vivo environment is required for the phenotype development. These data identify the actin nucleation regulator N-WASP as a novel element of hair-cycle control that modulates the antiproliferative and pro-apoptotic TGFβ pathway in keratinocytes in vivo and in vitro.

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Section: Differential Keratinocyte Gene Expression In the Absence Of mentioning

confidence: 99%

N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGFβ pathways

Lefever

Pedersen

Basse

et al. 2010

Journal of Cell Science

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“…Several lines of evidence suggest that the expression of HIF-1a by skin cells control the response of the organism to oxygen, and can play a major role in skin homeostasis (Cho et al, 2008;Liu et al, 2008;Michaylira and Nakagawa, 2006;Rezvani et al, 2011a). Epidermis and adnexae constitutionally express HIF-1a (Bedogni et al, 2005;Distler et al, 2004;Rosenberger et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Loss of epidermal hypoxia-inducible factor-1α accelerates epidermal aging and affects re-epithelialization in human and mouse

Rezvani

Ali

Serrano-Sanchez

et al. 2011

Journal of Cell Science

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SummaryIn mouse and human skin, HIF-1a is constitutively expressed in the epidermis, mainly in the basal layer. HIF-1a has been shown to have crucial systemic functions: regulation of kidney erythropoietin production in mice with constitutive HIF-1a epidermal deletion, and hypervascularity following epidermal HIF-1a overexpression. However, its local role in keratinocyte physiology has not been clearly defined. To address the function of HIF-1a in the epidermis, we used the mouse model of HIF-1a knockout targeted to keratinocytes (K14-Cre/Hif1a flox/flox ). These mice had a delayed skin phenotype characterized by skin atrophy and pruritic inflammation, partly mediated by basement membrane disturbances involving laminin-332 (Ln-332) and integrins. We also investigated the relevance of results of studies in mice to human skin using reconstructed epidermis and showed that HIF-1a knockdown in human keratinocytes impairs the formation of a viable reconstructed epidermis. A diminution of keratinocyte growth potential, following HIF-1a silencing, was associated with a decreased expression of Ln-322 and a6 integrin and b1 integrin. Overall, these results indicate a role of HIF-1a in skin homeostasis especially during epidermal aging.

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“…However, we previously found that epidermal keratinocytes uniquely express substantial amounts of HIF-1α even in normoxia. We also demonstrated that mitochondrial reactive oxygen species and the MEK/ERK pathway are involved in HIF-1α stabilization in keratinocytes [9]. In another study, we showed that UVB down-regulates HIF-1α by inhibiting the cap-dependent translation of HIF-1α [10].…”

Section: Discussionmentioning

confidence: 83%

“…We previously demonstrated that HIF-1α induces cell cycle arrest in keratinocytes by inducing p21 [9]. Thus, we examined whether Py-Zn induced p21 through HIF-1α ex- pression in keratinocytes, and found such an effect by Py-Zn (Fig.…”

Section: Pyrithione-zinc Induces P21 In Uvb-irradiated Keratinocytesmentioning

confidence: 99%

“…In addition to gene expression, HIF-1α plays a key role in controlling cancer cell growth under hypoxia; that is, HIF-1α sequesters MAX from the c-Myc/MAX complex, antagonizes the p21 gene-repressive action of c-Myc/MAX, and induces the p21 cell cycle inhibitor [8]. Likewise, HIF-1α plays a role in epidermal homeostasis by controlling the keratinocyte cell cycle through p21 expression [9]. Epidermal keratinocytes undergo cell cycle arrest in the G1 phase when they are cultured at high cell densities.…”

Section: Introductionmentioning

confidence: 99%

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Pyrithione-zinc Prevents UVB-induced Epidermal Hyperplasia by Inducing HIF-1α

Cho

Lee

Park

2010

Korean J Physiol Pharmacol

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Hippel-Lindau tumor suppressor protein; IRES, internal ribosome entry site; 5'-UTR, 5'-untranslated region; PI3K, phosphoinositide-3-kinase; mTOR, mammalian target of rapamycin; Akt, serine/threonine protein kinase; HSP, heat shock protein; MEK/ERK, mitogen-activated protein kinase kinase/extracellular signal-regulated kinase; HEK293, human embryonic kidney cell line 293; OTC, over-the-counter. Epidermal keratinocytes overgrow in response to ultraviolet-B (UVB), which may be associated with skin photoaging and cancer development. Recently, we found that HIF-1α controls the keratinocyte cell cycle and thereby contributes to epidermal homeostasis. A further study demonstrated that HIF-1α is down-regulated by UVB and that this process is involved in UVB-induced skin hyperplasia. Therefore, we hypothesized that the forced expression of HIF-1α in keratinocytes would prevent UVB-induced keratinocyte overgrowth. Among several agents known to induce HIF-1α , pyrithione-zinc (Py-Zn) overcame the UVB suppression of HIF-1α in cultured keratinocytes. Mechanistically, Py-Zn blocked the degradation of HIF-1α protein in keratinocytes, while it did not affect the synthesis of HIF-1α . Moreover, the p21 cell cycle inhibitor was down-regulated after UVB exposure, but was robustly induced by Py-Zn. In mice repeatedly irradiated with UVB, the epidermis became hyperplastic and HIF-1α disappeared from nuclei of epidermal keratinocytes. However, a cream containing Py-Zn effectively prevented the skin thickening and up-regulated HIF-1α to the normal level. These results suggest that Py-Zn is a potential agent to prevent UVB-induced photoaging and skin cancer development. This work also provides insight into a molecular target for treatment of UVB-induced skin diseases. Pyrithione-zinc Prevents UVB-induced Epidermal Hyperplasia by

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HIF-1α controls keratinocyte proliferation by up-regulating p21(WAF1/Cip1)

Cited by 49 publications

References 34 publications

N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGFβ pathways

N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGFβ pathways

Loss of epidermal hypoxia-inducible factor-1α accelerates epidermal aging and affects re-epithelialization in human and mouse

Pyrithione-zinc Prevents UVB-induced Epidermal Hyperplasia by Inducing HIF-1α

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