3611

ILK

ILK-2|P59;integrin-linked kinase;ILK;integrin-linked kinase

59 kDa serine/threonine-protein kinase|ILK-1|integrin-linked kinase-2|integrin-linked protein kinase|p59ILK

11p15.4

protein-coding

Although most reports describe the protein kinase integrin-linked kinase (ILK) as a proto-oncogene, occasional studies detail opposing functions in the regulationof normal and transformed cell proliferation, differentiation, and apoptosis. Here, we demonstrated that ILK functions as an oncogene in the highly aggressivepediatric sarcoma alveolar rhabdomyosarcoma (ARMS) and as a tumor suppressor in the related embryonal rhabdomyosarcoma (ERMS). These opposing functions hinge onsignaling through a noncanonical ILK target, JNK1, to the proto-oncogene c-Jun. RNAi-mediated depletion of ILK induced activation of JNK and its target, c-Jun, resulting in growth of ERMS cells, whereas in ARMS cells, it led to loss of JNK/c-Jun signaling and suppression of growth both in vitro and in vivo. Ectopicexpression of the fusion gene characteristic of ARMS (paired box 3-forkhead homolog in rhabdomyosarcoma [PAX3-FKHR]) in ERMS cells was sufficient to convertthem to an ARMS signaling phenotype and render ILK activity oncogenic. Furthermore, restoration of JNK1 in ARMS reestablished a tumor-suppressive function for ILK. These findings indicate what we believe to be a novel effectorpathway regulated by ILK, provide a mechanism for interconversion of oncogenic and tumor-suppressor functions of a single regulatory protein based on the genetic background of the tumor cells, and suggest a rationale for tailored therapy of rhabdomyosarcoma based on the different activities of ILK.

PURPOSE OF REVIEW: To review the 2008-2009 literature on pediatric genitourinarytumors and highlight the most significant publications. RECENT FINDINGS: New techniques such as gene expression profiling, PET, nephron-sparing surgery, and stem cell transplantation are being incorporated into contemporary treatments for pediatric patients with genitourinary tumors. The WTX gene is the most commonly mutated gene in Wilms tumor, and its product enhances Wilms tumor gene 1-mediated transcription. Germline WTX mutations cause an X-linked sclerosing bone dysplasia but do not appear to predispose to Wilms tumor formation. Protocadherin gene clusters on chromosome 5q31 may act as tumor suppressors. In rhabdomyosarcoma, ILK and platelet-derived growth factor receptor-A join the paired box gene 7 and3-forkhead box O1 fusions as potential therapeutic targets, and muscle-specific microRNAs offer promise as adjuvant therapy. Despite the high cure rate of Wilmstumor, long-term survivors remain at risk of death from various causes. SUMMARY:In general, the prognosis for patients with pediatric genitourinary tumors is favorable. The elucidation of the molecular abnormalities in these tumors is determining risk stratification, treatment strategies, and candidates for new drug development.