The Expression of Keratin K10 in the Basal Layer of the Epidermis Inhibits Cell Proliferation and Prevents Skin Tumorigenesis

Abstract

The inhibition of cell proliferation and Akt and PKC activities was also observed although to a minor extent in low hK10-expressing mice. These animals displayed no overt epidermal phenotype nor overexpression of K10. In these non-phenotypic mice, ectopic K10 expression also resulted in decreased skin tumorigenesis. Collectively, these data demonstrate that keratin K10 in vivo functions include the control of epithelial proliferation in skin epidermis.Keratins are the main components of the intermediate filament cytoskeleton in epithelial cells. They are a large family of proteins that includes ϳ30 different polypeptides expressed in a cell type-and differentiation-specific manner. Their functions have long been presumed to be predominantly structural. This role was clarified when human epithelial fragility syndromes became attributable to mutations within epidermal keratin genes (for reviews see Refs. 1-4). However, this shared function does not provide a clear explanation of the great diversity of these proteins, which suggests that they may have additional specific functions.Changes in keratin expression pattern are particularly important in the epidermis. Keratins K5 and K14 are expressed in the mitotically active basal cells. As these cells enter the terminal differentiation program, becoming postmitotic and suprabasal, keratins K5 and K14 are substituted by keratins K1 and K10 (5). Under the influence of hyperproliferative stimuli, for example during wound healing and in certain disorders including cancer, epidermal expression of K1 and K10 is drastically reduced. Keratins K6 and K16, normally absent from interfollicular epidermis, are, however, induced (6). As a whole, these changes suggest that each keratin pair provides specific functional requirements to epidermal keratinocytes. This is also highlighted by recent findings in which K16 was expressed ectopically (7) to rescue the epidermal fragility promoted by inactivation of the keratin K14 gene (8). These rescued animals show neither epidermal fragility nor neonatal mortality, but they exhibit strong phenotypic alterations such as alopecia, chronic epidermal ulcers, and alterations in other stratified epithelia (7). This demonstrates that these two proteins are not functionally equivalent.In search of specific keratin functions, we have shown that the forced expression of particular keratin polypeptides may influence proliferation in cultured cells. It has been specifically demonstrated that the ectopic expression of keratin K10 inhibits cell proliferation (9). The modulation of cell growth exerted by keratin K10 is linked to the retinoblastoma (pRb) protein and the molecular machinery controlling cell cycle progression during G 1 , in particular cyclin D1 expression (9). This activity appears to involve the sequestration of Akt/PKB and atypical PKC to the keratin cytoskeleton, mediated by keratin K10 through its amino terminus (10). Therefore, the presence of K10 leads to impaired phosphoinositide 3-kinase (PI3K) 1 signaling. Most of this information...

Unique and overlapping functions of pRb and p107 in the control of proliferation and differentiation in epidermis

“…4) might be of a particular relevance. Our recent work has demonstrated that this keratin may impose a cell cycle arrest in keratinocytes in a pRb-dependent manner (Paramio et al, 1999;Paramio et al, 2001a;Santos et al, 2002). Here, we show that K10-expressing cells do not exhibit a proliferative arrest.…”

“…Here, we show that K10-expressing cells do not exhibit a proliferative arrest. Given that K10 induces a cell cycle arrest in vivo and suppresses tumor development (Santos et al, 2002), the possible loop between pRb and K10 merits further investigation.…”

“…BrdU incorporation was monitored in formalin-fixed sections as described (Santos et al, 2002). Horseradish-peroxidase, Texas-Red-and FITC-conjugated secondary antibodies were purchased from Jackson and used 1/4000, 1/500 and 1/50 dilution, respectively.…”

“…Cryosections (8 µm) were prepared from skin samples embedded in OCT medium. For BrdU studies, mice were injected (0.1 mg/g weight) 1 hour prior to sacrifice (Santos et al, 2002).…”

Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output

“…S4). Previous studies showed that reduced Akt activity in TEC was responsible for altered thymic architecture, early involution and defects in keratinocyte proliferation [28][29][30] . In order to determine the implication of Akt in CYR61-mediated TEC proliferation, 2DG-FTOC were cultured with recombinant CYR61 in the presence of Akt inhibitor MK2206.…”