[Cell Cycle 6:23, 2928-2931, 1 December 2007]; ©2007 Landes Bioscience
Review
Ras/Erk MAPK Signaling in Epidermal Homeostasis and Neoplasia Thomas A. Khavari John Rinn*
Abstract
.
IST
Original manuscript submitted: 09/02/07 Manuscript accepted: 09/04/07
UT E
*Correspondence to: John Rinn; Program in Epithelial Biology; 269 Campus Drive, Room 2145; Stanford, California 94305 USA; Fax: 650.723.8762; Email:
[email protected]
RIB
Program in Epithelial Biology; Stanford University School of Medicine; Stanford, California USA
Epidermis provides the cutaneous barrier to the external environment and undergoes a continual process of proliferative self-renewal, with human epidermis undergoing complete turnover approximately 1,000 times in a lifetime. Recent work suggests that this ongoing proliferative replenishment of epidermal cells depends, in part, on continual signals for cell division and survival transmitted by the Ras/Erk MAPK pathway. Such constant cell proliferation, however, requires tight regulation to avoid the uncontrolled tissue expansion characteristic of epidermal neoplasia. Recent studies provide new insight into Ras/Erk MAPK pathway function in the control of normal skin development and homeostasis as well as how its deregulation promotes epidermal tumorigenesis.
OT D
Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/article/4998
Introduction
epidermis, proliferation, Ras, MAP kinase, Erk
The epidermis is the protective outer layer of skin comprised primarily of keratinocytes that give rise to the cutaneous barrier, and within which are embedded other cell types mediating processes such as pigmentation, immune responses and mechanoreception. Keratinocytes within the epidermis form four major layers (basal, squamous, granular and the outer cornified layer of the stratum corneum) that demonstrate a temporal and spatial regulation such that less differentiated cells (distinguished by keratin 5 and 14 expression) reside in the basal layer and progress through their life cycle into more distal and differentiated layers of the epithelium until finally reaching the stratum corneum. The innermost basal layer is adjacent to basement membrane containing key structures such as hemidesomosomes that are required to adhere the epidermis to the underlying dermis. The basal layer is also the major site of proliferation within the tissue. Basal keratin- ocytes migrate outwards to the squamous layer, which is characterized by induction of early differentiation markers, such as keratins 1 and 10. Late differentiation genes, such as loricrin, are expressed in the granular layer and the outermost layer, the stratum corneum, which form the barrier to the external environment. The constant progression of basal progenitor cells to the ultimate desquamation of the cornified layer demonstrates the need for continual self‑renewal of epidermal cells. The human epidermis self‑renews at a remarkable pace with estimated turnover occurring approximately once monthly.1 This demand for continual self‑renewal, if not tightly regulated, can go awry leading to disorders such as cancer or psoriasis. Conversely, too little proliferation may lead to epidermal atrophy and associated skin fragility and wounding. Thus, homeostasis in this context relies on a very precise balance between proliferation occurring in the inner, basement membrane‑proximal basal layer, and the programmed cell death which takes place at the outer granular‑to‑cornified layer transition. The purpose of this review is to summarize recent data on the classical Ras/Erk MAPK pathway in the control of epidermal homeostasis and neoplasia (Fig. 1). The mechanisms controlling epidermal homeostasis and neoplasia are still incompletely understood yet a number of proteins have been identified with non-redundant roles in this process. Genetic loss‑of‑function studies having revealed critical factors responsible for proliferation, differentiation or programmed cell death. Included among these are p63,2‑7 retinoic acid receptors,8,9 Notch proteins,10‑14 the epidermal growth factor receptor (EGFR),15 a‑catenin,19 the b1 integrin subunit,16,17 the b4 integrin subunit,18,19 as well as a numerous others.20 A number of these proteins function in part through activation of membrane‑bound Ras GTPases. For example, conditional knockout of the gene encoding a‑catenin leads to induction of Ras/Erk MAPK signaling and epidermal proliferation,
©
20
07
LA
ND
ES
BIO
SC
IEN
CE
.D
ON
Key words
2928
Cell Cycle
2007; Vol. 6 Issue 23
UT E RIB IST OT D
ON
suggesting that wound‑like disruption of adherens junctions stimulates cell division necessary for epidermal healing21 and potentially cancer. Cancers of the epidermis, including basal cell (BCC) and squamous cell carcinoma (SCC), represent the first and second most common cancers in the U.S., respectively.22 Several key regulators of cellular proliferation, including p53 and Ras, have been implicated in the pathogenesis of SCC. TP53 mutations are among the most common alterations found in human SCC tissue and are believed to facilitate neoplasia, in part, by abolishing restraints on further sunlight‑induced genomic injury.23 p53 mutations, however, are not sufficient to directly drive human epidermal tissue towards cancer,24 suggesting that other oncogenic changes play more potent roles in this process. Several lines of evidence point to RAS genes as key players in human epidermal carcinogenesis. First, as noted below, RAS is often mutated to an active form in cutaneous SCCs. Secondly Ras proteins are biochemically activated in a majority of human SCCs regardless of genetic RAS mutation status. Finally they play a central role in experimental murine models of SCC. The critical Ras GTPases were originally identified from Harvey and Kirsten strains of rat sarcoma viruses and found to have cellular proto‑oncogene homologs, H‑Ras and K‑Ras respectively.25 Mammalian K‑Ras is alternately spliced in its last codons, resulting in 2 isoforms K‑Ras4A and K‑Ras4B, with the latter exhibiting more amino acid diversity than other Ras proteins. The third known proto‑oncogene homolog of RAS is N‑Ras that was initially isolated from human neuroblastoma. Since that time, many additional oncogenes and Ras superfamily members have been identified but classical Ras genes remain among those most frequently mutated in human cancer, with an estimated frequency of up to 30% of all human tumors analyzed. Oncogenic Ras point mutations commonly affect codons 12, 13 or 61, leading to constitutive GTP‑binding and activation.25 Additional mechanisms of Ras activation occur in human tumors independent of activating point mutations, including Ras gene amplification and activation of wild‑type Ras protein by aberrantly overactive upstream activators, such as receptor tyrosine kinases. In a series of 416 human SCCs, at least one Ras isoform, with HRAS the most common, contained activating mutations in codons 12, 13 or 61 in 22% of cancers (COSMIC somatic mutations in cancer database; www.sanger.ac.uk/genetics/CGP/cosmic/), and in prior studies Ras mutation rates have ranged from figures lower than this to as high as 46% of SCCs studied.26 We have recently shown that even SCCs lacking any HRAS, KRAS or NRAS mutations display increased levels of active Ras‑GTP in a majority of cases.27,28 Data generated in an array of murine genetic models, including classical DMBA/TPA multistage carcinogenesis in mouse skin, also indicate that Ras plays a pivotal role in initiating SCC development.29 Together these data point to Ras and its downstream effectors as critical regulators in epidermal neoplasia. Characterization of Ras and its downstream targets has provided important clues as to how misregulation of the pathway leads to neoplasia. Ras isoforms share 100% amino acid identity in the first 85 N‑terminal residues, and more divergent C‑termini. They exist as 21 kDa proteins that can bind to a variety of intracellular membranes30 via lipid modifications by prenyl transferases that include farnesyl and geranyl‑geranyl moieties at the conserved C‑terminal CAAX motif. Ras proteins transmit signals from a number of cell surface
.
Ras/MAPK in Homeostasis and Neoplasia
CE
.D
Figure 1. The classical Ras/Erk MAPK pathway plays a major regulatory role in epidermal homeostasis and neoplasia. Typical levels of Ras/Erk signaling (arrow) results in epidermal homeostasis with the rate of proliferation in equilibrium with differentiation. On the other hand over activation (bold arrow) leads to either senescence or neoplasia in conjunction with G1 escape.
©
20
07
LA
ND
ES
BIO
SC
IEN
receptors. These include growth factor receptors, such as EGFR, and extracellular matrix receptors, such as integrins. These receptors convey signals to Ras via adaptors such as Grb2 and Gab1 as well as nucleotide exchange factors such as SOS.31 Ras exerts its effects via discrete downstream effector pathways that classically include Raf/Mek/Erk mitogen activated protein kinases (MAPKs), type I phosphatidylinositol‑3 kinases (PI3Ks) and Ral guanine nucleotide exchange factors (RalGEFs) along with a host of additional pathways involving proteins such as AF6, Tiam, Rin1, Nore1 as well as protein kinase C and phospholipase C isoforms.32 These pathways appear to function differentially in discrete cell and tissue settings. For example, Ras induces PI3K and its downstream effector Akt in some, but not all, cell types to promote survival. In mammals, the best characterized Ras effector pathways proceed via a MAPK cascade that includes Raf MAPKKKs (Raf1, B‑Raf and A‑Raf ), MEK MAPKKs (Mek1 and Mek2), and Erk MAPKs (Erk1 and Erk2).33 As the mechanistic details of the Ras pathway continue to emerge we will have a better understanding of the therapeutic potential of blocking misregulated Ras signalling. The classical Ras/Erk MAPK pathway plays major roles in develop- ment, homeostasis (Fig. 1), cancer and transmits signals from cell surface receptors to affect nuclear gene regulation and a host of other intracellular processes.34,35 The importance of the pathway in human development has been demonstrated by involvement of numerous cascade components in an array of related hereditary human clinical disorders, including Costello, Noonan and cardio‑facio‑cutaneous (CFC) syndromes.25 In the latter condition, for example, mutations
www.landesbioscience.com
Cell Cycle
2929
Ras/MAPK in Homeostasis and Neoplasia
OT D
IST
RIB
UT E
.
the marked epidermal hypo‑proliferation and increased epidermal apoptosis observed during development. Profound decreases in cell division within the epidermal basal layer were observed from E15.5 through the neonatal period. In adult tissue, conditional deletion of Mek1 on a Mek2‑deficient background led to epidermal apoptosis and tissue death, indicating that the primary effect of Mek MAPKK loss relates to tissue viability in this setting. Epidermal death seen with combined Mek1/2 loss was associated with alterations in the pro‑apoptotic protein, BAD. Diminished levels of the inhibitory phosphorylation of BAD on residue serine 112, a known direct target of Erk MAPK pathway action, were observed in epidermis. However, the functional importance of altered BAD activity in this context remains to be established. Additionally, increased apoptosis in tumors was observed upon conditional deletion of the retinoblastoma protein.50 Taken together, these loss‑of‑function experiments support a model in which the Ras/Erk MAPK pathway both stimulates as well as sustains normal epidermal proliferation and viability. The potential importance of Ras/Erk MAPK signaling in the control of normal epidermal proliferation raised the question as to how the pathway might help drive cell division in epidermal cancer. Over‑expression of oncogenic Ras or Raf alone in keratinocytes in culture caused cell cycle arrest in G1 phase, in spite of induction of cyclin D1 expression. This arrest was accompanied by suppressed Cdk4 protein levels and could be rescued by maintaining Cdk4 expression in this setting.24,51 Unlike epidermal tissue expressing active Ras, Raf or Mek alone, which became hyperplastic but not neoplastic in vivo, tissue also maintaining Cdk4 expression displayed accelerated proliferation and rapid global conversion to invasive neoplasia indistinguishable from SCC in weeks. This process could be mimicked by other interventions that sustained Cdk4 expression, including NFkB blockade and activation of the JNK MAPK pathway.27,52 These findings are consistent with findings in transgenic mice engineered for Cdk4 over‑expression in epidermis. Cdk4 transgenic epidermis displayed a higher rate of skin tumor formation, with Cdk4 observed to replace the role of tumor promoters.53 These data support a model in which Ras Erk MAPK signaling in epidermis induces cyclin D1, but requires other pathways that ultimately sustain Cdk4 protein expression to drive neoplastic proliferation. In summary, the Ras/Erk MAPK pathway plays a central and non-redundant role in sustaining proliferation and viability of mammalian epidermis. The pathway also exerts potent pro‑tumorigenic effects. Thus Ras/Erk MAPK pathway is a double‑edged sword that is required for normal epidermal survival and proliferative self‑renewal but which, if overactive can cause cellular transformation to cancer (Fig. 1). In both contexts, the pathway appears to act most effectively within the cells most competent to respond, namely those within the basal layer adherent to the underlying epidermal basement membrane. The full array of end effectors of Ras/Erk MAPK signaling in mediating effects on promoting cell division and preventing apoptosis in epidermis are not yet known.54 Potential targets for the former include well‑characterized cell cycle genes, such as cyclin D1, and for the latter, BAD. Further studies are needed to definitively define the functional targets of Ras/Erk MAPK signaling in these processes and to determine if loss of Erk1 and Erk2 MAPKs phenocopies loss of Mek1 and Mek2 MAPKK components of the pathway.
©
20
07
LA
ND
ES
BIO
SC
IEN
CE
.D
ON
in Ras, Raf and Mek genes all produce similar clinical abnormalities, underscoring the coherence of the pathway in human development. The Ras/Erk MAPK cascade alters >140 target proteins and can affect a pleiotropic array of cellular functions, including proliferation, differentiation, survival, and migration. Proteins in the pathway interact with a host of scaffolding and regulatory mediators, such as KSR, p14, MP1, RKIP, Cnk, IQGAP1 and 14‑3‑3 proteins. Defining the relative contributions of the Ras/Erk MAPK cascade and its targets, as well as the role of other Ras effector pathways, in epithelial tumorigenesis remains an area of active investigation. Initial in vitro studies provided conflicting results regarding the role of Ras/Erk MAPK signaling in epidermal keratinocyte growth and differentiation, however, subsequent work in tissue models has demonstrated that activation of the cascade promotes epidermal proliferation and inhibits differentiation. Several authors reported that constitutive activation of Ras/Raf inhibited cell division and induced differentiation in murine keratinocytes.36,37 Other studies reported the opposite,38‑40 underscoring the need for in vivo studies. Gain‑of‑function efforts with the Ras/Erk MAPK have primarily been conducted in transgenic mice. Constitutive expression of active Ras proteins in the basal layer cells of epidermal tissue via promoters for keratins 5 and 14 during development leads to epidermal hyper‑proliferation and impaired differentiation; expression of active Ras in suprabasal layers, however, produces a far milder response, limited in some cases to focal hyperplasia at sites of trauma.41‑45 These data indicate that cellular competence to respond to Ras signaling differs within different sites within the epidermis, with the basal layer most sensitive to Ras effects. Models using constitutive activation of Ras suffered from lethality in transgenic mice expressing Ras mutants in the basal layer, prompting efforts to generate conditional activation of the pathway in tissue post‑development. Fusion of mutant estrogen receptor ligand binding domains to Ras, Raf and Mek proteins generated conditionally active proteins that inducibly and reversibly stimulated epidermal proliferation and inhibited differentiation to different degrees, with Ras and Raf being most potent in the approaches used.46,47 Conditional activation of Ras, Raf and Mek proteins induced additional changes, including induction of proliferation‑ associated keratins 6 and 16 as well as upregulation of the proliferation‑stimulating b1 integrin subunit. These data in- dicated that induction of Ras/Erk MAPK signaling in vivo stimulated proliferation, however, they did not, by the nature of their design, address whether this pathway is normally required for these processes. Loss‑of‑function experiments have subsequently determined that elements of the Ras/Erk MAPK pathway are required for normal epidermal cell division and viability.48 Constitutive expression of a dominant‑negative H‑Ras led to epidermal hypo‑proliferation and enhanced differentiation, precisely the opposite effects of Ras/ Raf/Mek gain‑of‑function, suggesting that intact Ras action may be required for normal proliferative self‑renewal in the epidermis. To determine if the Ras/Erk MAPK cascade is indeed required for proliferative homeostasis of the epidermis, genetic ablation of the MAPKKs (Mek1 and Mek2) of the cascade was recently undertaken.49 Combined epidermal loss of both Mek1 and Mek2 proved lethal, with mice dying from defects in cutaneous barrier function. These defects were associated with epidermal hypoplasia and surface regions devoid of differentiating keratinocytes, possibly due to 2930
Cell Cycle
2007; Vol. 6 Issue 23
Ras/MAPK in Homeostasis and Neoplasia
IST
RIB
UT E
.
30. Rocks O, Peyker A, Bastiaens PI. Spatio‑temporal segregation of Ras signals: One ship, three anchors, many harbors. Curr Opin Cell Biol 2006; 18:351‑7. 31. Mitin N, Rossman KL, Der CJ. Signaling interplay in Ras superfamily function. Curr Biol 2005; 15:R563‑74. 32. Rajalingam K, Schreck R, Rapp UR, Albert S. Ras oncogenes and their downstream targets. Biochim Biophys Acta 2007. 33. Libra M, Malaponte G, Bevelacqua V, Siciliano R, Castrogiovanni P, Fulvi A, Micali G, Ligresti G, Mazzarino MC, Stivala F, Travali S, McCubrey JA. Absence of BRAF gene mutation in non-melanoma skin tumors. Cell Cycle 2006; 5:968‑70. 34. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature 2001; 410:37‑40. 35. Meloche S, Pouyssegur J. The ERK1/2 mitogen‑activated protein kinase pathway as a master regulator of the G1‑ to S‑phase transition. Oncogene 2007; 26:3227‑39. 36. Lin AW, Lowe SW. Oncogenic ras activates the ARF‑p53 pathway to suppress epithelial cell transformation. Proc Natl Acad Sci USA 2001; 98:5025‑30. 37. Roper E, Weinberg W, Watt FM, Land H. p19ARF‑independent induction of p53 and cell cycle arrest by Raf in murine keratinocytes. EMBO Rep 2001; 2:145‑50. 38. Mainiero F, Murgia C, Wary KK, Curatola AM, Pepe A, Blumemberg M, Westwick JK, Der CJ, Giancotti FG. The coupling of alpha6beta4 integrin to Ras‑MAP kinase pathways mediated by Shc controls keratinocyte proliferation. Embo J 1997; 16:2365‑75. 39. Zhu AJ, Haase I, Watt FM. Signaling via beta1 integrins and mitogen‑activated protein kinase determines human epidermal stem cell fate in vitro. Proc Natl Acad Sci USA 1999; 96:6728‑33. 40. Dlugosz AA, Cheng C, Williams EK, Dharia AG, Denning MF, Yuspa SH. Alterations in murine keratinocyte differentiation induced by activated rasHa genes are mediated by protein kinase C‑alpha. Cancer Res 1994; 54:6413‑20. 41. Brown K, Strathdee D, Bryson S, Lambie W, Balmain A. The malignant capacity of skin tumours induced by expression of a mutant H‑ras transgene depends on the cell type targeted. Curr Biol 1998; 8:516‑24. 42. Dajee M, Tarutani M, Deng H, Cai T, Khavari PA. Epidermal Ras blockade demonstrates spatially localized Ras promotion of proliferation and inhibition of differentiation. Oncogene 2002; 21:1527‑38. 43. Greenhalgh DA, Rothnagel JA, Quintanilla MI, Orengo CC, Gagne TA, Bundman DS, Longley MA, Roop DR. Induction of epidermal hyperplasia, hyperkeratosis, and papillomas in transgenic mice by a targeted v‑Ha‑ras oncogene. Mol Carcinog 1993; 7:99‑110. 44. Greenhalgh DA, Quintanilla MI, Orengo CC, Barber JL, Eckhardt JN, Rothnagel JA, Roop DR. Cooperation between v‑fos and v‑rasHA induces autonomous papillomas in transgenic epidermis but not malignant conversion. Cancer Res 1993; 53:5071‑5. 45. Bailleul B, Surani MA, White S, Barton SC, Brown K, Blessing M, Jorcano J, Balmain A. Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter. Cell 1990; 62:697‑708. 46. Tarutani M, Cai T, Dajee M, Khavari PA. Inducible activation of ras and raf in adult epidermis. Cancer Res 2003; 63:319‑23. 47. Scholl FA, Dumesic PA, Khavari PA. Mek1 alters epidermal growth and differentiation. Cancer Res 2004; 64:6035‑40. 48. Galabova‑Kovacs G, Kolbus A, Matzen D, Meissl K, Piazzolla D, Rubiolo C, Steinitz K, Baccarini M. ERK and beyond: Insights from B‑Raf and Raf‑1 conditional knockouts. Cell Cycle 2006; 5:1514‑8. 49. Scholl FA, Dumesic PA, Barragan DI, Harada K, Bissonauth V, Charron J, Khavari PA. Mek1/2 MAPK kinases are essential for Mammalian development, homeostasis, and Raf‑induced hyperplasia. Dev Cell 2007; 12:615‑29. 50. Ruiz S, Santos M, Paramio JM. Is the loss of pRb essential for the mouse skin carcinogenesis? Cell Cycle 2006; 5:625‑9. 51. Lazarov M, Green CL, Zhang JY, Kubo Y, Dajee M, Khavari PA. Escaping G1 restraints on neoplasia—Cdk4 regulation by Ras and NF‑kappa B. Cell Cycle 2003; 2:79‑80. 52. Zhang JY, Adams AE, Ridky TW, Tao S, Khavari PA. Tumor necrosis factor receptor 1/ c‑Jun‑NH2‑kinase signaling promotes human neoplasia. Cancer Res 2007; 67:3827‑34. 53. Miliani de Marval PL, Macias E, Conti CJ, Rodriguez‑Puebla ML. Enhanced malignant tumorigenesis in Cdk4 transgenic mice. Oncogene 2004; 23:1863‑73. 54. de Gruijl FR, Mullenders LH, Stout GJ. Elimination of keratinocytes stagnant in s‑phase through epidermal turnover instead of in situ apoptosis. Cell Cycle 2006; 5:565‑6.
©
20
07
LA
ND
ES
BIO
SC
IEN
CE
.D
ON
OT D
References 1. Fuchs E, Raghavan S. Getting under the skin of epidermal morphogenesis. Nat Rev Genet 2002; 3:199‑209. 2. Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 1999; 398:708‑13. 3. Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C, McKeon F. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 1999; 398:714‑8. 4. Senoo M, Pinto F, Crum CP, McKeon F. p63 is essential for the proliferative potential of stem cells in stratified epithelia. Cell 2007; 129:523‑36. 5. Koster MI, Dai D, Marinari B, Sano Y, Costanzo A, Karin M, Roop DR. p63 induces key target genes required for epidermal morphogenesis. Proc Natl Acad Sci USA 2007; 104:3255‑60. 6. Truong AB, Kretz M, Ridky TW, Kimmel R, Khavari PA. p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Genes Dev 2006; 20:3185‑97. 7. Vigano MA, Lamartine J, Testoni B, Merico D, Alotto D, Castagnoli C, Robert A, Candi E, Melino G, Gidrol X, Mantovani R. New p63 targets in keratinocytes identified by a genome‑wide approach. Embo J 2006; 25:5105‑16. 8. Li M, Indra AK, Warot X, Brocard J, Messaddeq N, Kato S, Metzger D, Chambon P. Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature 2000; 407:633‑6. 9. Li M, Chiba H, Warot X, Messaddeq N, Gerard C, Chambon P, Metzger D. RXR‑alpha ablation in skin keratinocytes results in alopecia and epidermal alterations. Development 2001; 128:675‑88. 10. Blanpain C, Lowry WE, Pasolli HA, Fuchs E. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev 2006; 20:3022‑35. 11. Mammucari C, Tommasi di Vignano A, Sharov AA, Neilson J, Havrda MC, Roop DR, Botchkarev VA, Crabtree GR, Dotto GP. Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control. Dev Cell 2005; 8:665‑76. 12. Pan Y, Lin MH, Tian X, Cheng HT, Gridley T, Shen J, Kopan R. Gamma‑secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell 2004; 7:731‑43. 13. Lowell S, Jones P, Le Roux I, Dunne J, Watt FM. Stimulation of human epidermal differentiation by delta‑notch signalling at the boundaries of stem‑cell clusters. Curr Biol 2000; 10:491‑500. 14. Nickoloff BJ, Qin JZ, Chaturvedi V, Denning MF, Bonish B, Miele L. Jagged‑1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF‑kappaB and PPARgamma. Cell Death Differ 2002; 9:842‑55. 15. Sibilia M, Wagner EF. Strain‑dependent epithelial defects in mice lacking the EGF receptor. Science 1995; 269:234‑8. 16. Brakebusch C, Grose R, Quondamatteo F, Ramirez A, Jorcano JL, Pirro A, Svensson M, Herken R, Sasaki T, Timpl R, Werner S, Fassler R. Skin and hair follicle integrity is crucially dependent on beta 1 integrin expression on keratinocytes. EMBO Journal 2000; 19:3990‑4003. 17. Raghavan S, Bauer C, Mundschau G, Li Q, Fuchs E. Conditional ablation of beta1 integrin in skin: Severe defects in epidermal proliferation, basement membrane formation, and hair follicle invagination. J Cell Biol 2000; 150:1149‑60. 18. Dowling J, Yu QC, Fuchs E. Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. J Cell Biol 1996; 134:559‑72. 19. Murgia C, Blaikie P, Kim N, Dans M, Petrie HT, Giancotti FG. Cell cycle and adhesion defects in mice carrying a targeted deletion of the integrin beta4 cytoplasmic domain. Embo J 1998; 17:3940‑51. 20. Hafner C, Vogt T, Hartmann A. FGFR3 mutations in benign skin tumors. Cell Cycle 2006; 5:2723‑8. 21. Vasioukhin V, Bauer C, Degenstein L, Wise B, Fuchs E. Hyperproliferation and defects in epitheial polarity upon conditional ablation of alpha‑catenin in skin. Cell 2001; 104:605‑17. 22. Alam M, Ratner D. Cutaneous squamous‑cell carcinoma. N Engl J Med 2001; 344:975‑83. 23. Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, Remington L, Jacks T, Brash DE. Sunburn and p53 in the onset of skin cancer. Nature 1994; 372:773‑6. 24. Lazarov M, Kubo Y, Cai T, Dajee M, Tarutani M, Lin Q, Fang M, Tao S, Green CL, Khavari PA. CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis. Nat Med 2002; 8:1105‑14. 25. Schubbert S, Bollag G, Shannon K. Deregulated Ras signaling in developmental disorders: New tricks for an old dog. Curr Opin Genet Dev 2007; 17:15‑22. 26. Pierceall WE, Goldberg LH, Tainsky MA, Mukhopadhyay T, Ananthaswamy HN. Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog 1991; 4:196‑202. 27. Dajee M, Lazarov M, Zhang JY, Cai T, Green CL, Russell AJ, Marinkovich MP, Tao S, Lin Q, Kubo Y, Khavari PA. NF‑kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 2003; 421:639‑43. 28. To MD, Perez‑Losada J, Mao JH, Balmain A. Crosstalk between Pten and Ras signaling pathways in tumor development. Cell Cycle 2005; 4:1185‑8. 29. Woodworth CD, Michael E, Smith L, Vijayachandra K, Glick A, Hennings H, Yuspa SH. Strain‑dependent differences in malignant conversion of mouse skin tumors is an inherent property of the epidermal keratinocyte. Carcinogenesis 2004; 25:1771‑8.
www.landesbioscience.com
Cell Cycle
2931
