• Transcription factors regulate cell proliferation and differentiation

Kwok-Ming Yao is currently Associate Professor in the School of Biomedical Sciences, The University of Hong Kong. He graduated from Brandeis University (Genetics, Molecular and Developmental Biology program) with a PhD degree in 1992.  After postdoctoral training at Dana Farber Cancer Institute and Harvard Medical School (1993-1994) and then Genetics Institute, Inc., Cambridge, MA (1994-1996), he joined the University of Hong Kong as Assistant Professor in 1997 and was promoted to Associate Professor in 2009. He has published more than 40 peer-reviewed articles including papers in Science, Molecular and Cellular Biology, Journal of Biological Chemistry, The EMBO Reports, Journal of Cell Science, Diabetes and Endocrinology.

FOXM1 and regulation of cancer and stem cell function
Dr. Yao cloned FOXM1 when he was a postdoctoral fellow at GeneticsInstitute, Inc. (GI). His lab first demonstrated that FOXM1 over-expressionstimulates cyclin B1 expression and enhances progression through the G2/M phase of the cellcycle. FOXM1 was later shown by Dr. Yao’s lab to be regulated byMAPK signaling, strongly indicating a pivotal role played by FOXM1 in mediating thegrowth promoting effect of mitogens. Further, Dr. Yao and his collaboratorsdiscovered that FOXM1 regulates the transcription of the estrogen receptor a in breast cancercells and is involved in the regulation of cervical cancer progression and themigration/invasion of ovarian cancer cells, and that FoxM1 counteracts oxidative stress-inducedsenescence and stimulates Bmi-1 expression in mouse embryonic fibroblasts. Recently, Dr. Yao’slab presented evidence to support the hypothesis that the b isoform, which is frequentlyover-expressed in cancers, represents a more active form of FOXM1. Most recently, Dr. Yao has initiated collaboration with Prof Y Tan (Hunan U) to investigate the role of FOXM1 in the regulation of genome stability and pluripotency in human embryonic stem cells.

PDZ Domain-containing protein 2 (PDZD2) and regulation of pancreatic b-cell formation
Dr. Yao also cloned PDZD2 as a highly expressed gene in pancreatic beta cells when he was a postdoctoral fellow at GI. PDZD2, with a relative molecular mass of approximately 300 kDa, contains six different PDZ protein–protein interaction domains, which are thought to act as molecular scaffolds to facilitate the assembly of macromolecular complexes. Dr. Yao’s lab demonstrated that PDZD2 is proteolytically cleaved by caspase-3 to generate the secreted protein, sPDZD2. This is analogous to the processing of pro-IL-16 to generate the secreted cytokine, IL-16. Expression of sPDZD2 in pancreas and other tissues suggests an extracellular signaling function for sPDZD2. Dr. Yao and his collaborators showed that sPDZD2 exists at high levels in human fetal pancreas and in pancreatic progenitor cells derived from human fetus. Recent studies revealed that depletion of both the full-length and secreted forms of PDZD2 in rat insulin-secreting INS-1E cells led to dramatic attenuation of mRNA expression of Insulin1, Glut2 and MafA, whereas addition of recombinant sPDZD2 (at 10-10 M) stimulated the expression of these beta-cell genes and the activity of the insulin promoter. Interestingly, depletion of the full-length form (but not the secreted form) of PDZD2 in two gene-trap mutant mouse lines led to increased basal insulin secretion, revealing a novel role for PDZD2 in the regulation of basal insulin secretion probably via modulation of KATP channel activity

 

 

 

1. Ngan AWL, Tsui MG, So DHF, Leung WY, Chan DW and Yao KM (2019) Novel nuclear partnering role of EPS8 with FOXM1 in regulating cell proliferation. Front. Oncol. Mar 19;9:154. doi:10.3389/fonc.2019.00154.
2. Kwok CT, Leung MH, Qin J, Qin Y, Wang J, Lee YL and Yao KM (2016) The Forkhead box transcription factor FOXM1 is required for the maintenance of cell proliferation and protection against oxidative stress in human embryonic stem cells. Stem Cell Res. 16(3):651-661. doi: 10.1016/j.scr.2016.03.007.7.
3. Chan DW, Hui WW, Wang JJ, Yung MM, Hui LM, Qin Y, Liang RR, Leung TH, Xu D, Chan KK, Yao KM, Tsang BK and Ngan HY (2016) DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling. Oncogene, doi: 10.1038/onc.2016.307.
4. Lam AK, Ngan AW, Leung MH, Kwok DC, Liu VW, Chan DW, Leung WY and Yao KM (2013) FOXM1b, which is present at elevated levels in cancer cells, has a greater transforming potential than FOXM1c. Front. Oncol. 3:11. doi: 10.3389/fonc.2013.00011.
5. Cui J, Wang Z, Cheng Q, Lin R, Xin-Mei Z, Leung PS, Copeland NG, Jenkins NA, Yao KM and Huang JD (2011) Targeted inactivation of kinesin-1 in pancreatic ß–cells in vivo leads to insulin secretory deficiency. Diabetes 60: 320-30.
6. Tsang SW, Shao D, Cheah KSE, Okuse K, Leung PS and Yao KM (2010) Increased basal insulin secretion in Pdzd2-deficient mice. Mol. Cell Endocrinol. 315: 263-270.
7. Li SK, Smith DK, Leung WY, Cheung AM, Lam EW, Dimri GP and Yao KM (2008) FoxM1c counteracts oxidative stress-induced senescence and stimulates Bmi-1 expression. J. Biol. Chem. 283: 16545-16553.
8. Tam CW, Cheng AS, Ma RY, Yao KM and Shiu SY (2006) Inhibition of prostate cancer cell growth by human secreted PDZ domain-containing protein 2, a potential autocrine prostate tumor suppressor. Endocrinology 147(11):5023-5033.
9. Ma RYM, Tong THK, Cheung AMS, Tsang ACC, Leung WY, and Yao KM (2005) Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c. J. Cell Sci. 118: 795-806.
10. Yeung ML, Tam TSM, Tsang ACC and Yao KM (2003) Proteolytic cleavage of PDZD2 generates a secreted peptide containing two PDZ domains. EMBO Rep. 4: 412-418.
11. Yao KM,  Sha M, Lu Z, and Wong GG (1997) Molecular analysis of a novel winged helix protein, WIN (later renamed FOXM1). Expression pattern, DNA binding property, and alternative splicing within the DNA binding domain. J. Biol. Chem. 272: 19827-19836.

Recent Research Grants as Principal Investigator:

• 2020-2023: Investigating GPR161 as receptor of secreted PDZD2 in the negative regulation of Hedgehog signaling during early development, GRF (RGC), HK$1,195,542.
• 2019-2022: PDZD2 and primary open-angle glaucoma: Characterization of Pdzd2-deficient mice and human PDZD2 SNPs, HMRF, HK$1,499,628.

• Holders of three patents
• Consultant to Genetics Institute, Cambridge, MA, USA from 1996 to 1998
• Invited reviewer of FOXM1 network in NCI-Nature Pathway Interaction Database and Springer Science on book chapter “Epigenetics of Aging"
• Review Editor in Frontiers in Molecular and Cellular Oncology; Invited Reviewer of journals (Biochimica et Biophysica Acta – Molecular Cell Research, Cancer Gene Therapy, Cancer Letters, FEBS Letters, Frontiers in Oncology, Frontiers in Microbiology, Frontiers in Molecular Neuroscience, Hepatology, Journal of Molecular Endocrinology, Molecular Cancer Research, PLoS ONE, Scientific Reports, etc.)
• Invited Reviewer for Grant agencies – National Science Foundation (USA) CAREER Program Review, The French National Research Agency (ANR), Cancer Research UK Project Grant Application Review, Genesis Oncology Trust (New Zealand), Hong Kong Baptist University Research Committee
• Supervision of Research Postgraduate Students: 19 PhD, 17 MPhil, 7 MMedSc