Loss of p120 catenin and links to mitotic alterations, inflammation, and skin cancer

TY - JOUR

T1 - Loss of p120 catenin and links to mitotic alterations, inflammation, and skin cancer

AU - Perez-Moreno, Mirna

AU - Song, Weimin

AU - Pasolli, H Amalia

AU - Williams, Scott E

AU - Fuchs, Elaine

PY - 2008/10/7

Y1 - 2008/10/7

N2 - Tumor formation involves epigenetic modifications and microenvironmental changes as well as cumulative genetic alterations encompassing somatic mutations, loss of heterozygosity, and aneuploidy. Here, we show that conditional targeting of p120 catenin in mice leads to progressive development of skin neoplasias associated with intrinsic NF-kappaB activation. We find that, similarly, squamous cell carcinomas in humans display altered p120 and activated NF-kappaB. We show that epidermal hyperproliferation arising from p120 loss can be abrogated by IkappaB kinase 2 inhibitors. Although this underscores the importance of this pathway, the role of NF-kappaB in hyperproliferation appears rooted in its impact on epidermal microenvironment because as p120-null keratinocytes display a growth-arrested phenotype in culture. We trace this to a mitotic defect, resulting in unstable, binucleated cells in vitro and in vivo. We show that the abnormal mitoses can be ameliorated by inhibiting RhoA, the activity of which is abnormally high. Conversely, we can elicit such mitotic defects in control keratinocytes by elevating RhoA activity. The ability of p120 deficiency to elicit mitotic alterations and chronic inflammatory responses, that together may facilitate the development of genetic instability in vivo, provides insights into why it figures so prominently in skin cancer progression.

AB - Tumor formation involves epigenetic modifications and microenvironmental changes as well as cumulative genetic alterations encompassing somatic mutations, loss of heterozygosity, and aneuploidy. Here, we show that conditional targeting of p120 catenin in mice leads to progressive development of skin neoplasias associated with intrinsic NF-kappaB activation. We find that, similarly, squamous cell carcinomas in humans display altered p120 and activated NF-kappaB. We show that epidermal hyperproliferation arising from p120 loss can be abrogated by IkappaB kinase 2 inhibitors. Although this underscores the importance of this pathway, the role of NF-kappaB in hyperproliferation appears rooted in its impact on epidermal microenvironment because as p120-null keratinocytes display a growth-arrested phenotype in culture. We trace this to a mitotic defect, resulting in unstable, binucleated cells in vitro and in vivo. We show that the abnormal mitoses can be ameliorated by inhibiting RhoA, the activity of which is abnormally high. Conversely, we can elicit such mitotic defects in control keratinocytes by elevating RhoA activity. The ability of p120 deficiency to elicit mitotic alterations and chronic inflammatory responses, that together may facilitate the development of genetic instability in vivo, provides insights into why it figures so prominently in skin cancer progression.

KW - Animals

KW - Catenins

KW - Cell Adhesion Molecules

KW - Cell Proliferation

KW - Immunohistochemistry

KW - Inflammation

KW - Mice

KW - Mice, Transgenic

KW - Mitosis

KW - NF-kappa B

KW - Phosphoproteins

KW - Skin

KW - Skin Neoplasms

KW - rho GTP-Binding Proteins

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1073/pnas.0807301105

DO - 10.1073/pnas.0807301105

M3 - Journal article

C2 - 18809907

SN - 0027-8424

VL - 105

SP - 15399

EP - 15404

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 40

ER -