碱性螺旋-环-螺旋(Basic helix-loop-helix protein,bHLH)家族成员Twist2对间质细胞系的发生和发育起转录调节作用,经直接或间接机制发挥分子开关功能,从而激活或抑制靶基因。Twist2能直接结合DNA上 E-box保守序列,招募共激活物或抑制剂;能与E蛋白调节因子发生蛋白-蛋白相互作用,干扰激活或抑制功能。Twist2无义突变导致Setleis综合征。对Twist2的早期研究多集中在骨骼发育,随后在多种肿瘤中发现其有表达差异,研究表明Twist2在肿瘤的上皮-间质转化(Epithelial-mesenchymal transition,EMT)中发挥着重要作用。Twist2参与了多条通路的调控,其调控作用的发挥受到时空表达、磷酸化、二聚化和细胞定位的调节,在机体的正常发育、体内平衡和疾病发生机制中研究Twist2的作用显得尤为重要。文章对Twist2在成骨分化、肿瘤形成和EMT中的作用及其分子机制进行综述,以便帮助了解Twist2的生物学功能,为进一步在疾病的诊断、发展、以及治疗等方面的转化应用研究提供依据。
Twist2, one of the basic helix-loop-helix protein (bHLH) family members, is responsible for the transcriptional regulation in mesenchymal cell lineages during its development. Twist2 functions as a molecular switch to activate or repress target genes by direct or indirect mechanisms. Twist2 can directly bind with conserved E-box on DNA sequence, to recruit co-activators or repressors, and interfere with the activation or inhibition function through protein-protein interactions with E-protein modulators. Nonsense mutations of Twist2 cause Setleis syndrome. Early research on Twist2 focused on osteogenesis, and then expression differences were found in a wide variety of tumors. Further studies showed that Twist2 plays an important role in cancer epithelial-mesenchymal transition (EMT). Regulation function of Twist2 is controlled by temporal and spatial expression, phosphorylation, dimerization and cell positioning adjustment. The involvement of Twist2 in a broad spectrum of regulatory pathways highlights the importance of understanding its role in normal development, homeostasis and disease. In this review, we summarize the role of Twist2 in osteogenesis differentiation, tumor formation and EMT, and its molecular mechanism. It is helpful to have a thorough understanding of the biological functions of Twist2, and facilitate the transformation and application in diagnosis, development and therapy.
[1] Li L, Cserjesi P, Olson EN. Dermo-1: a novel twist- related bHLH protein expressed in the developing dermis. Dev Biol , 1995, 172(1): 280-292.
[2] Gitelman I. Evolution of the vertebrate twist family and synfunctionalization: a mechanism for differential gene loss through merging of expression domains. Mol Biol Evol , 2007, 24(9): 1912-1925.
[3] Šošić D, Richardson JA, Yu K, Ornitz DM, Olson EN. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-κB activity. Cell , 2003, 112(2): 169-180.
[4] Perrin-Schmitt F, Bolcato-Bellemin AL, Bourgeois P, Stoetzel C, Danse JM. The locations of the H-twist and H-dermo-1 genes are distinct on the human genome. Biochim Biophys Acta , 1997, 1360(1): 1-2.
[5] Benezra R, Davis RL, Lockshon D, Turner DL, Weintraub H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell , 1990, 61(1): 49-59.
[6] Lee MS, Lowe G, Flanagan S, Kuchler K, Glackin CA. Human Dermo-1 has attributes similar to twist in early bone development. Bone , 2000, 27(5): 591-602.
[7] Tukel T, Šošić D, Al-Gazali LI, Erazo M, Casasnovas J, Franco HL, Richardson JA, Olson EN, Cadilla CL, Desnick RJ. Homozygous nonsense mutations in TWIST2 cause Setleis syndrome. Am J Hum Genet , 2010, 87(2): 289-296.
[8] Tamura M, Noda M. Identification of DERMO-1 as a member of helix-loop-helix type transcription factors expressed in osteoblastic cells. J Cell Biochem , 1999, 72(2): 167-176.
[9] Zhang Y, Hassan MQ, Li ZY, Stein JL, Lian JB, van Wijnen AJ, Stein GS. Intricate gene regulatory networks of helix-loop-helix (HLH) proteins support regulation of bone- tissue related genes during osteoblast differentiation. J Cell Biochem , 2008, 105(2): 487-496.
[10] Osathanon T, Ritprajak P, Nowwarote N, Manokawinchoke J, Giachelli C, Pavasant P. Surface-bound orientated Jagged-1 enhances osteogenic differentiation of human periodontal ligament-derived mesenchymal stem cells. J Biomed Mater Res A , 2013, 101(2): 358-367.
[11] Huang YY, Meng T, Wang SZ, Zhang H, Mues G, Qin CL, Feng JQ, D'Souza RN, Lu YB. Twist1- and twist2-haploinsufficiency results in reduced bone formation. PLoS One , 2014, 9(6): e99331.
[12] Franco HL,Casasnovas J, Rodríguez-Medina JR, Cadilla CL. Redundant or separate entities?-roles of Twist1 and Twist2 as molecular switches during gene transcription. Nucleic Acids Res , 2011, 39(4): 1177-1186.
[13] Fang X, Cai Y, Liu J, Wang Z, Wu Q, Zhang Z, Yang CJ, Yuan L, Ouyang G. Twist2 contributes to breast cancer progression by promoting an epithelial-mesenchymal transition and cancer stem-like cell self-renewal. Oncogene , 2011, 30(47): 4707-4720.
[14] Ansieau S, Bastid J, Doreau A, Morel AP, Bouchet BP, Thomas C, Fauvet F, Puisieux I, Doglioni C, Piccinin S, Maestro R, Voeltzel T, Selmi A, Valsesia-Wittmann S, Caron DFC, Puisieux A. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell , 2008, 14(1): 79-89.
[15] Liang XH, Zheng M, Jiang JA, Zhu GQ, Yang J, Tang YL. Hypoxia-inducible factor-1 α, in association with TWIST2 and SNIP1, is a critical prognostic factor in patients with tongue squamous cell carcinoma. Oral Oncol , 2011, 47(2): 92-97.
[16] Gasparotto D, Polesel J, Marzotto A, Colladel R, Piccinin S, Modena P, Grizzo A, Sulfaro S, Serraino D, Barzan L, Doglioni C, Maestro R. Overexpression of TWIST2 correlates with poor prognosis in head and neck squamous cell carcinomas. Oncotarget , 2011, 2(12): 1165-1175.
[17] Zhou CC, Liu JR, Tang YL, Zhu GQ, Zheng M, Jiang J, Yang J, Liang XH. Coexpression of hypoxia-inducible factor-2α, TWIST2, and SIP1 may correlate with invasion and metastasis of salivary adenoid cystic carcinoma. J Oral Pathol Med , 2012, 41(5): 424-431.
[18] Shimoda M, Sugiura T, Imajyo I, Is
