Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis

Abstract

SUMMARYAbnormal activation of Hedgehog (Hh) signaling leads to basal cell carcinoma (BCC) of the skin, the most common human cancer. Gli2, the major transcriptional activator of Hh signaling, is essential for hair follicle development and its overexpression in epidermis induces BCC formation and maintains tumor growth. Despite its importance in skin development and tumorigenesis, little is known about the molecular regulation of Gli2. Sufu and Kif7 are two evolutionarily conserved regulators of Gli transcription factors. Here, we show that Sufu and Kif7 regulate Gli2 through distinct mechanisms in keratinocytes. Sufu restricts the activity of Gli2 through cytoplasmic sequestration. Kif7 possesses Sufu-dependent and -independent regulatory functions in Hh signaling: while it promotes Hh pathway activity through the dissociation of Sufu-Gli2 complex, it also contributes to the repression of Hh target genes in the absence of Sufu. Deletion of both Sufu and Kif7 in embryonic skin leads to complete loss of follicular fate. Importantly, although inactivation of Sufu or Kif7 alone in adult epidermis cannot promote BCC formation, their simultaneous deletion induces BCC. These studies establish Sufu and Kif7 as crucial components in the regulation of Gli2 localization and activity, and illustrate their overlapping functions in skin development and tumor suppression.

Kif7 is required for the patterning and differentiation of the diaphragm in a model of syndromic congenital diaphragmatic hernia

“…Consistent with previous reports, the expression of Ptch1, the SHH receptor, was not detected. Kif7 is a key regulator of Hh signaling in neural tube (19), limb (20), bone (27), and skin development (28), and Hh signaling promotes cell proliferation in several systems by regulating the expression of the cell cycle regulating gene, Cyclin D1 (Ccnd1) (11). Hence, we examined the expression and counted the number of Ccnd1 + cells in the E12.5 diaphragms of Kif7 dd/dd mutant embryos, and we determined that the number of Ccnd1 + cells was increased approximately twofold compared with cells in littermate controls (Fig.…”

Prognostic impact of the expression of Hedgehog proteins in cervical carcinoma FIGO stages I–IV treated with radiotherapy or chemoradiotherapy

“…Structure-function analyses have shown that C-terminal sequences are required for positive inducing activity and cytoplasmic localization, whereas N-terminal sequences determine dominant negative function and nuclear localization [22]. There are two important regulators of the GLI proteins, Sufu that forms complex with GLI proteins and prevents its nuclear accumulation, and Kif7 that promotes activation through dissociation of Sufu-GLI2 complexes to allow translocation of GLI2 into the nucleus [23]. The strong predictive and prognostic value of GLI2 in our series, in contrast to GLI1 and GLI3, supports this assumption.…”

From Normal Development to Disease: The Biochemistry and Regulation of GLI2

“…The full-length GLI2 is bound to SuFu, and thus SuFu keeps GLI2 tethered in the cytoplasm [7,9,10] . Another member of the pathway, Kif7, can antagonize SuFu by disrupting the SuFu/GLI2 complex and allowing nuclear translocation of GLI2 [80] . The absence of Hh signaling results in the predominance of GLI2 protein maintained in a repressive state while active Hh signaling reverses this repression.…”