Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis - PubMed (original) (raw)
. 2012 Nov;139(22):4152-61.
doi: 10.1242/dev.081190. Epub 2012 Oct 3.
Affiliations
- PMID: 23034632
- DOI: 10.1242/dev.081190
Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis
Zhu Juan Li et al. Development. 2012 Nov.
Abstract
Abnormal 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.
Similar articles
- Kif7 promotes hedgehog signaling in growth plate chondrocytes by restricting the inhibitory function of Sufu.
Hsu SH, Zhang X, Yu C, Li ZJ, Wunder JS, Hui CC, Alman BA. Hsu SH, et al. Development. 2011 Sep;138(17):3791-801. doi: 10.1242/dev.069492. Epub 2011 Jul 27. Development. 2011. PMID: 21795282 - GLI2-specific transcriptional activation of the bone morphogenetic protein/activin antagonist follistatin in human epidermal cells.
Eichberger T, Kaser A, Pixner C, Schmid C, Klingler S, Winklmayr M, Hauser-Kronberger C, Aberger F, Frischauf AM. Eichberger T, et al. J Biol Chem. 2008 May 2;283(18):12426-37. doi: 10.1074/jbc.M707117200. Epub 2008 Mar 3. J Biol Chem. 2008. PMID: 18319260 Free PMC article. - FOXE1, a new transcriptional target of GLI2 is expressed in human epidermis and basal cell carcinoma.
Eichberger T, Regl G, Ikram MS, Neill GW, Philpott MP, Aberger F, Frischauf AM. Eichberger T, et al. J Invest Dermatol. 2004 May;122(5):1180-7. doi: 10.1111/j.0022-202X.2004.22505.x. J Invest Dermatol. 2004. PMID: 15140221 - Basal cell carcinoma and the carcinogenic role of aberrant Hedgehog signaling.
Saran A. Saran A. Future Oncol. 2010 Jun;6(6):1003-14. doi: 10.2217/fon.10.49. Future Oncol. 2010. PMID: 20528237 Review. - Molecular conversations and the development of the hair follicle and basal cell carcinoma.
Harris PJ, Takebe N, Ivy SP. Harris PJ, et al. Cancer Prev Res (Phila). 2010 Oct;3(10):1217-21. doi: 10.1158/1940-6207.CAPR-10-0210. Epub 2010 Sep 21. Cancer Prev Res (Phila). 2010. PMID: 20858758 Free PMC article. Review.
Cited by
- The Hedgehog pathway: role in cell differentiation, polarity and proliferation.
Jia Y, Wang Y, Xie J. Jia Y, et al. Arch Toxicol. 2015 Feb;89(2):179-91. doi: 10.1007/s00204-014-1433-1. Epub 2015 Jan 6. Arch Toxicol. 2015. PMID: 25559776 Free PMC article. Review. - KIF7 attenuates prostate tumor growth through LKB1-mediated AKT inhibition.
Wong KY, Liu J, Chan KW. Wong KY, et al. Oncotarget. 2017 Apr 26;8(33):54558-54571. doi: 10.18632/oncotarget.17421. eCollection 2017 Aug 15. Oncotarget. 2017. PMID: 28903364 Free PMC article. - Down-regulation of Gli transcription factor leads to the inhibition of migration and invasion of ovarian cancer cells via integrin β4-mediated FAK signaling.
Chen Q, Xu R, Zeng C, Lu Q, Huang D, Shi C, Zhang W, Deng L, Yan R, Rao H, Gao G, Luo S. Chen Q, et al. PLoS One. 2014 Feb 12;9(2):e88386. doi: 10.1371/journal.pone.0088386. eCollection 2014. PLoS One. 2014. PMID: 24533083 Free PMC article. - Obesity-associated variants within FTO form long-range functional connections with IRX3.
Smemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gómez-Marín C, Aneas I, Credidio FL, Sobreira DR, Wasserman NF, Lee JH, Puviindran V, Tam D, Shen M, Son JE, Vakili NA, Sung HK, Naranjo S, Acemel RD, Manzanares M, Nagy A, Cox NJ, Hui CC, Gomez-Skarmeta JL, Nóbrega MA. Smemo S, et al. Nature. 2014 Mar 20;507(7492):371-5. doi: 10.1038/nature13138. Epub 2014 Mar 12. Nature. 2014. PMID: 24646999 Free PMC article. - Suppressor of fused (Sufu) represses Gli1 transcription and nuclear accumulation, inhibits glioma cell proliferation, invasion and vasculogenic mimicry, improving glioma chemo-sensitivity and prognosis.
Liu X, Wang X, Du W, Chen L, Wang G, Cui Y, Liu Y, Dou Z, Wang H, Zhang P, Chang L, Yi L, Cai J, Jiang C. Liu X, et al. Oncotarget. 2014 Nov 30;5(22):11681-94. doi: 10.18632/oncotarget.2585. Oncotarget. 2014. PMID: 25373737 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Miscellaneous