Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

TY - JOUR

T1 - Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

AU - Wang, Z

AU - Pedersen, Esben Ditlev Kølle

AU - Basse, A

AU - Lefever, T

AU - Peyrollier, K

AU - Kapoor, S

AU - Mei, Q

AU - Karlsson, R

AU - Chrostek-Grashoff, A

AU - Brakebusch, C

N1 - Keywords: 9,10-Dimethyl-1,2-benzanthracene; Animals; Cell Proliferation; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Genes, ras; Keratinocytes; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Neuropeptides; Proto-Oncogene Proteins c-akt; Skin Neoplasms; Tetradecanoylphorbol Acetate; p21-Activated Kinases; p38 Mitogen-Activated Protein Kinases; rac GTP-Binding Proteins

PY - 2010/6/10

Y1 - 2010/6/10

N2 - Rac1 has a role in proliferation and survival of tumor cells in vitro. The exact effects of Rac1 on growth, apoptosis and corresponding signaling pathways during tumorigenesis in vivo, however, have not been explored yet. Using mice with a keratinocyte-restricted deletion of the Rac1 gene, we found that Rac1 is essential for DMBA/TPA-induced skin tumor formation. This corresponded to a decreased keratinocyte hyperproliferation, although apoptosis was not detectably altered. Activated Rac1 promoted Erk-dependent hyperproliferation by Pak1-mediated Mek activation independent of Mek1 phosporylation at serine 298. Rac1 was furthermore required for Pak2-dependent hyperactivation of Akt, which under in vivo condition was restricted to the suprabasal cell layers corresponding to a suprabasal-specific expression of Pak2. It is surprising that none of these signaling pathways was altered in untreated Rac1-deficient skin, indicating a hyperproliferation-specific function of Rac1 in vivo. These data suggest that blocking of Rac1 function might allow tumor-specific growth repression, as Rac1 is not required for normal growth and growth signaling controlling pathways in skin in vivo.

AB - Rac1 has a role in proliferation and survival of tumor cells in vitro. The exact effects of Rac1 on growth, apoptosis and corresponding signaling pathways during tumorigenesis in vivo, however, have not been explored yet. Using mice with a keratinocyte-restricted deletion of the Rac1 gene, we found that Rac1 is essential for DMBA/TPA-induced skin tumor formation. This corresponded to a decreased keratinocyte hyperproliferation, although apoptosis was not detectably altered. Activated Rac1 promoted Erk-dependent hyperproliferation by Pak1-mediated Mek activation independent of Mek1 phosporylation at serine 298. Rac1 was furthermore required for Pak2-dependent hyperactivation of Akt, which under in vivo condition was restricted to the suprabasal cell layers corresponding to a suprabasal-specific expression of Pak2. It is surprising that none of these signaling pathways was altered in untreated Rac1-deficient skin, indicating a hyperproliferation-specific function of Rac1 in vivo. These data suggest that blocking of Rac1 function might allow tumor-specific growth repression, as Rac1 is not required for normal growth and growth signaling controlling pathways in skin in vivo.

U2 - 10.1038/onc.2010.95

DO - 10.1038/onc.2010.95

M3 - Journal article

C2 - 20383193

SN - 0950-9232

VL - 29

SP - 3362

EP - 3373

JO - Oncogene

JF - Oncogene

IS - 23

ER -