Hu, Yinling

Hu, Yinling Ph.D.

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Research Interests

Keratinocyte differentiation, proliferation, death and tumorigenesis

Current Research

My laboratory interest is to understand IκB kinase α (IKKα) related keratinocyte differentiation, proliferation, death, and carcinogenesis. We previously demonstrated that IKKα loss in mice results in malformed skeleton and epidermis. The epidermis of IKKα-/- skin lacks granular and cornified cell layers and displays striking hyperplasia. The phenotypes imply that IKKα may play both roles in cell differentiation and cell proliferation in epidermis. During the last year, we focused on two aspects:

  1. We previously reported that a large proportion of aggressive squamous cell carcinomas of humans and mice express markedly reduced IKKa. However, the role of IKKa in maintaining genomic stability is unknown. We recently reported that IKKa deficient keratinocytes had a defect in the G2/M cell cycle arrest in response to DNA damage due to downregulated 14-3-3s, a cell cycle checkpoint protein. Trimethylated histone H3 lysine 9 (H3-K9) was found to associate with the histone trimethyltransferase Suv39h1 and DNA methyltransferase Dnmt3a in the methylated 14-3-3s locus. Reintroduction of IKKa restored the expression of 14-3-3s. IKKa was found to associate with H3 in 14-3-3s, which prevented access of Suv39h1 to H3, thereby preventing hypermethylation of 14-3-3s. IKKa mutants that failed to bind to H3 did not restore the expression of 14-3-3s. Thus, IKKa protects the 14-3-3s locus from hypermethylation, which serves as a mechanism of maintaining genomic stability in keratinocytes.
  2. We previously reported a marked reduction in IKKa expression in a large proportion of human poorly-differentiated squamous cell carcinomas (SCCs) and the occurrence of Ikka mutations in human SCCs. Also, overexpression of IKKa in the epidermis inhibited the development of skin carcinomas and metastases in mice. However, whether a reduction in IKKa expression promotes skin tumor development is currently unknown. We recently assessed the susceptibility of Ikka hemizygotes to chemical carcinogen-induced skin carcinogenesis. Ikka+/- mice developed 2 times more papillomas and 11 times more carcinomas than did Ikka+/+ mice. The tumors were larger in Ikka+/- than in Ikka+/+ mice, but tumor latency was shorter in Ikka+/- than in Ikka+/+ mice. Some of the Ikka+/- papillomas and most Ikka+/- carcinomas lost the remaining Ikka wild-type allele. Somatic Ikka mutations were detected in carcinomas and papillomas. The chemical carcinogen-induced H-Ras mutations were detected in all the tumors. The phorbol ester tumor promoter induced higher mitogenic and angiogenic activities in Ikka+/- than in Ikka+/+ skin. These elevated activities were intrinsic to keratinocytes, suggesting that a reduction in IKKa expression provided a selective growth advantage, which cooperated with H-Ras mutations to promote papilloma formation. Furthermore, excessive ERK and IKK kinase activities were observed in carcinomas compared to those in papillomas. Thus, the combined mitogenic, angiogenic, and IKK activities might contribute to malignant conversion. Our findings provide evidence that a reduction in IKKa expression promotes the development of papillomas and carcinomas and that the integrity of the Ikka gene is required for suppressing skin carcinogenesis.

Selected Publications

  1. Lomada D, Liu B, Coghlan L, Hu Y, Richie ER. Thymus medulla formation and central tolerance are restored in IKKalpha-/- mice that express an IKKalpha transgene in keratin 5+ thymic epithelial cells, J Immunol, 178 (2), 829-37, 2007
  2. Park E, Zhu F, Liu B, Xia X, Shen J, Bustos T, Fischer SM, Hu Y. Reduction in IkappaB kinase alpha expression promotes the development of skin papillomas and carcinomas, Cancer Res, 67 (19), 9158-68, 2007
  3. Zhu F, Xia X, Liu B, Shen J, Hu Y, Person M, Hu Y. IKKalpha shields 14-3-3sigma, a G(2)/M cell cycle checkpoint gene, from hypermethylation, preventing its silencing, Mol Cell, 27 (2), 214-27, 2007
  4. Liu B, Park E, Zhu F, Bustos T, Liu J, Shen J, Fischer SM, Hu Y. A critical role for I kappaB kinase alpha in the development of human and mouse squamous cell carcinomas, Proc Natl Acad Sci U S A, 103 (46), 17202-7, 2006
  5. Hu Y, Baud V, Oga T, Kim KI, Yoshida K, Karin M. IKKalpha controls formation of the epidermis independently of NF-kappaB, Nature, 410 (6829), 710-4, 2001
  6. Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway, Science, 293 (5534), 1495-9, 2001
  7. Hu Y, Baud V, Delhase M, Zhang P, Deerinck T, Ellisman M, Johnson R, Karin M. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase, Science, 284 (5412), 316-20, 1999

Contact Information


Mailing Address: P.O. Box 389, Smithville, Texas 78957
Physical Address: 1808 Park Road 1C, Smithville, Texas 78957
Phone: (512) 237-9577