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Published 22 November 2004. doi:10.1083/jcb.200404018
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 4, 745-756
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Article

 Integrin {alpha}v-mediated inactivation of p53 controls a MEK1-dependent melanoma cell survival pathway in three-dimensional collagen

Wenjie Bao and Staffan Strömblad

Department of Laboratory Medicine, Karolinska Institutet, Stockholm, 141 86 Sweden

Correspondence to Staffan Strömblad: staffan.stromblad{at}labmed.ki.se; or Wenjie Bao: wenjie.bao{at}labmed.ki.se

Integrin {alpha}v is required for melanoma cell survival and tumor growth in various models. To elucidate integrin {alpha}v-mediated melanoma cell survival mechanisms, we used a three-dimensional (3D) collagen gel model mimicking the pathophysiological microenvironment of malignant melanoma in the dermis. We found that integrin {alpha}v inactivated p53 and that suppression of p53 activity by dominant negative p53 or p53-small interfering RNA obviated the need for integrin {alpha}v for melanoma cell survival in 3D-collagen and for tumor growth in vivo. This indicates that integrin {alpha}v-mediated inactivation of p53 functionally controls melanoma cell survival. Furthermore, we found that melanoma cell integrin {alpha}v was required for MAPK kinase (MEK) 1 and extracellular signal-regulated kinase (ERK)1/2 activity in 3D-collagen, whereas inhibition of MEK1 activity induced apoptosis. Surprisingly, MEK1 and ERK1/2 activities were restored in integrin {alpha}v-negative melanoma cells by suppression of p53, whereas concomitant block of MEK1 induced apoptosis. This suggests that integrin {alpha}v controls melanoma cell survival in 3D-collagen through a pathway involving p53 regulation of MEK1 signaling.

Abbreviations used in this paper: 2D, two-dimensional; 3D, three-dimensional; ca, constitutively active; dn, dominant negative; EMSA, electrophoretic mobility shift analysis; ERK, extracellular signal-regulated kinase; MEK, MAPK kinase; s.c., subcutaneously; siRNA, small interfering RNA.


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