Aberrant GLI1 Activation in DNA Damage Response, Carcinogenesis and Chemoresistance
| Autor: | Chinnadurai Mani, Mohammad Athar, Komaraiah Palle, Kaushlendra Tripathi |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
GLI1 Review medicine.disease_cause lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine GLI2 medicine 030304 developmental biology Protein Patched Homolog 1 0303 health sciences biology Wnt signaling pathway chemoresistance lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens hedgehog signaling Hedgehog signaling pathway 3. Good health Oncology PTCH1 030220 oncology & carcinogenesis Cancer research biology.protein DNA damage Smoothened Carcinogenesis carcinogenesis |
| Zdroj: | Cancers Cancers, Vol 7, Iss 4, Pp 2330-2351 (2015) |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers7040894 |
| Popis: | The canonical hedgehog (HH) pathway is a multicomponent signaling cascade (HH, protein patched homolog 1 (PTCH1), smoothened (SMO)) that plays a pivotal role during embryonic development through activation of downstream effector molecules, namely glioma-associated oncogene homolog 1 (GLI1), GLI2 and GLI3. Activation of GLIs must be tightly regulated as they modulate target genes which control tissue patterning, stem cell maintenance, and differentiation during development. However, dysregulation or mutations in HH signaling leads to genomic instability (GI) and various cancers, for example, germline mutation in PTCH1 lead to Gorlin syndrome, a condition where patients develop numerous basal cell carcinomas and rarely rhabdomyosarcoma (RMS). Activating mutations in SMO have also been recognized in sporadic cases of medulloblastoma and SMO is overexpressed in many other cancers. Recently, studies in several human cancers have shown that GLI1 expression is independent from HH ligand and canonical intracellular signaling through PTCH and SMO. In fact, this aberrantly regulated GLI1 has been linked to several non-canonical oncogenic growth signals such as Kirsten rat sarcoma viral oncogene homolog (KRAS), avian myelocytomatosis virus oncogene cellular homolog (C-MYC), transforming growth factor β (TGFβ), wingless-type MMTV integration site family (WNT) and β-catenin. Recent studies from our lab and other independent studies demonstrate that aberrantly expressed GLI1 influences the integrity of several DNA damage response and repair signals, and if altered, these networks can contribute to GI and impact tumor response to chemo- and radiation therapies. Furthermore, the ineffectiveness of SMO inhibitors in clinical studies argues for the development of GLI1-specific inhibitors in order to develop effective therapeutic modalities to treat these tumors. In this review, we focus on summarizing current understanding of the molecular, biochemical and cellular basis for aberrant GLI1 expression and discuss GLI1-mediated HH signaling on DNA damage responses, carcinogenesis and chemoresistance. |
| Databáze: | OpenAIRE |
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