Granular cell tumors are benign neurally derived neoplasms, involving cutaneous and subcutaneous tissues; and typically occur as solitary lesions. Multiple granular cell tumors occur in 10% of affected individuals, but are in children. Children with underlying somatic and genetic syndromes, including neurofibromatosis and Noonan syndrome, appear to be at higher risk of developing multiple granular cell tumors. Skin biopsy assists in diagnosis, since granular cell tumors have a similar appearance to other cutaneous nodules. Painful or rapidly growing granular cell tumors should be excised and asymptomatic non-growing granular cell tumors may be observed. Children with multiple granular cell tumors should have a complete physical examination to rule out an underlying genetic syndrome.

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Mullerian-inhibiting substance (MIS), a transforming growth factor-B family member, activates the nuclear factor-KB (NF-KB) pathway and induces the expression of B-cell translocation gene 2 (BTG2), IFN regulatory factor-1 (IRF-1), and the chemokine Gro-B. Inhibiting NF-KB activation with a phosphorylation-deficient IKBA mutant abrogated MIS-mediated induction of all three genes. Expression of dominant-negative Smad1, in which serines at the COOH-terminal SSVS motif are converted to alanines, suppressed MIS-induced Smad1 phosphorylation and impaired MIS-stimulated Gro-B promoterdriven reporter expression and Gro-B mRNA. Suppressing Smad1 expression using small interfering RNA also mitigated MIS-induced Gro-B mRNA, suggesting that regulation of Gro-B expression by MIS was dependent on activation of NF-KB as well as Smad1. However, induction of IRF-1 and BTG2 mRNAs by MIS was independent of Smad1 activation. Characterization of KB-binding sequences within Gro-B, BTG2, and IRF-1 promoters showed that MIS stimulated binding of p50 and p65 subunits to all three sites, whereas phosphorylated Smad1 (phospho-Smad1) protein was detectable only in the NF-KB complex bound to the KB site of the Gro-B promoter. Consistent with these observations, chromatin immunoprecipitation assays showed recruitment of both phospho-Smad1 and p65 to the Gro-B promoter in vivo, whereas p65, but not phospho-Smad1, was recruited to the BTG2 promoter. These results show a novel interaction between MIS-stimulated Smad1 and NF-KB signaling in which enhancement of NF-KB DNA binding and gene expression by phospho-Smad1 is dependent on the sequence of the KB consensus site within the promoter. [Cancer Res 2007;67(6):2747-56]

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