HIF-2a promotes hypoxic cell proliferation by enhancing c-Myc transcriptional activity (Cancer Cell, 2007, 11:335-347)

報告日期: 2007/10/26
報告時間: 16:00/16:50
報告學生: 林君杰
講評老師: 蔡少正
附件下載:

HIF-2a Promotes Hypoxic Cell Proliferation by Enhancing c-Myc Transcriptional Activity

Authors: John D. Gordan, Jessica A. Bertout, Cheng-Jun Hu, J. Alan Diehl, and M. Celeste Simon.

Journal: Cancer Cell 11, 335–347, 2007

Student: Chun-Chieh Lin

Commentator: Prof. Shaw-Jenq Tsai

Time: 16:00 – 17:00, 26 Oct, 2007.

Room 602

Abstract:

  Hypoxia induces tumor angiogenesis, invasion and metastasis. Hypoxia-response genes expression is majorly regulated by hypoxia-induced factors (HIFs). The HIF a subunits, HIF-1a and HIF-2a, both can form heterodimers with b subunit respectively to regulate downstream genes expression by binding hypoxia response elements (HREs). Previous studies show that HIF-1a induces cell-cycle arrest by antagonizing c-Myc binding function with Sp1, Miz1 and Max transcription factors. HIF-2a promotes VHL-null renal cell carcinoma (RCC) but the mechanism is not clear, whereas HIF-1a inhibits the growth of RCC. The authors hypothesized that HIF-2a promotes cell-cycle progression by enhancing c-Myc functions under hypoxia. Western blot and BrdU analysis showed that overexpression of HIF-2a not only promoted cell-cycle progression not only in RCC cells but in NIH3T3 cells and mouse primary embryo fibroblasts. Increased expression level of HIF-2a improved c-Myc binding activity to its target gene promoters by ChIP assay, and HIF-2a stablized c-Myc in forming complexes with Sp1, Miz1, and Max, respectively. QRT-PCR results showed c-Myc could upregulate target genes which promote cell-cycle progression. Taken together, the authors suggest that HIF-2a enhances c-Myc functions to promote cell-cycle progression.

Reference:

1. Cheng-Jun Hu, Li-Yi Wang, Lewis A. Chodosh, Brian Keith, and M. Celeste Simon. Differential Roles of Hypoxia-Inducible Factor 1a (HIF-1a) and HIF-2a in Hypoxic Gene Regulation. MOLECULAR AND CELLULAR BIOLOGY, 2003, p. 9361–9374.

2. Minori Koshiji, Yukio Kageyama, Erin A Pete, Izumi Horikawa, J Carl Barrett and L Eric Huang. HIF-1a induces cell cycle arrest by functionally counteracting Myc. The EMBO Journal, 2004, 23, 1949–1956.

3. Minori Koshiji, Kenneth K.-W. To, Kensuke Kumamoto, Paul Modrich, and L. Eric Huang. HIF-1a Induces Genetic Instability by Transcriptionally Downregulating MutS Expression. Molecular Cell, 2005, Vol. 17, 793–803.