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High mobility group A1 protein acts as a new target of Notch1 signaling and regulates cell proliferation in T leukemia cells

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Abstract

Active mutations of Notch1 play pivotal roles during leukemogenesis, but the downstream targets and molecular mechanisms of activated Notch1 signaling have not yet been fully clarified. In this study, we detected the overexpression of the high mobility group A1 (HMGA1) and activation of Notch1 signaling in mouse thymic lymphomas. A direct regulation of Notch1 on HMGA1 transcription was demonstrated and two Notch1/RBPJ cobinding sites of T/CTCCCACA were found in HMGA1 promoter regions. It was the first time demonstrated that HMGA1 was the downstream target of Notch1 signaling. Moreover, knockdown of HMGA1 resulted in significantly impaired cell growth and decreased expressions of cyclin D and cyclin E in human T leukemia cells. The formation of complexes was also observed between HMGA1 and retinoblastoma (RB) protein indicating a mechanism of cell cycle regulation. These findings suggest that activated HMGA1 regulates cell proliferation through the Notch1 signaling pathway, which represents an important molecular pathway leading to leukemogenesis.

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Acknowledgments

This study was supported by National Natural Science Foundation of China (81070887, 81101538), Grants from South-Central University for Nationalities (YZZ09007 and XTZ10001), and by the K.C. Wong Magna Fund in Ningbo University.

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Authors and Affiliations

  1. Medical School, Ningbo University, Ningbo, 315211, China

    Yang Xi

  2. Department of Pharmacology, College of Pharmacy, South-Central University for Nationalities, No.708, Minyuan Road, Wuhan, 430074, Hubei, China

    Yu-Sang Li & He-Bin Tang

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  1. Yang Xi
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  3. He-Bin Tang
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Correspondence to Yu-Sang Li.

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11010_2012_1517_MOESM1_ESM.pdf

Supplementary Figure 1. Notch1/RBPJ cobinding sites of T/CTCCCACA in human HMGA1 promoter region within 2 kb of transcriptional start site (TSS). Two Notch1/RBPJ cobinding sites of T/CTCCCACA were found and underline. The genome sequence was downloaded from the Homo sapiens chromosome 6 genomic contig, GRCh37.p9 Primary Assembly (NCBI Reference Sequence: NT_007592.15)

11010_2012_1517_MOESM2_ESM.pdf

Supplementary Figure 2. Decreased HMGA1 expression in C-MYC knockdwon leukemia cells. Quantitative RT-PCR analysis of C-MYC and HMGA1 expression after siRNA transfected human T-ALL HPB-ALL cells. β-actin was used as the internal control. The mRNA in GL3 siRNA treated cells was normalized to 1. P values (Student’s t test) for the differences between GL3 control and C-MYC siRNA treated samples are indicated. *(P<0.05); **(P<0.01)

Supplementary Table 1. Quantitative RT-PCR primers

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Xi, Y., Li, YS. & Tang, HB. High mobility group A1 protein acts as a new target of Notch1 signaling and regulates cell proliferation in T leukemia cells. Mol Cell Biochem 374, 173–180 (2013). https://doi.org/10.1007/s11010-012-1517-2

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  • DOI: https://doi.org/10.1007/s11010-012-1517-2

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