Regulation of urokinase receptor expression in colon cancer

Summary

Principal Investigator: Douglas Boyd
Abstract: A strong body of work has implicated the cell surface urokinase receptor (u-PAR) in modulating tumor growth and progression. Elevated u-PAR levels yield increased growth while low u-PAR promotes tumor dormancy the latter protective against microenvironmental stress such as hypoxia, nutrient deprivation. The u- PAR also binds the serine protease urokinase thus increasing plasmin formation and extracellular matrix protein turnover to promote tumor cell migration/invasion. Paradoxically, diminished u-PAR-dependent proteolysis benefits thrombus-enveloped tumor cells by virtue of maintaining the integrity of the fibrin "cloaking" the tumor cells from lymphokine-activated killer cells. We have made the intriguing observation that in some colon cancer cells, clonal populations oscillate in u-PAR display between high and low cell surface density with reduced tumorigenecity segregating with the latter. Interestingly, the altered u-PAR cell surface display is posttranslational in nature. In Specific Aim #1 we will determine the prevalence of u-PAR display plasticity in colon cancer, if altered tumorigenecity/dormancy mirrors this oscillation in cell surface u-PAR density and whether the sub-population down-shifted to low u-PAR has an advantage with respect to protection from the killing activity of LAK cells. In Specific Aim # 2, we will determine whether altered glycosylation of u-PAR in the u-PARdeficient population is an initial stimulus for lysosomal degradation of the immature protein.
Funding Period: ----------------1994 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Histone H3 acetylation and H3 K4 methylation define distinct chromatin regions permissive for transgene expression
    Chunhong Yan
    Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
    Mol Cell Biol 26:6357-71. 2006
  2. ncbi Identification of an histone H3 acetylated/K4-methylated-bound intragenic enhancer regulatory for urokinase receptor expression
    H Wang
    Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
    Oncogene 26:2058-70. 2007
  3. ncbi A novel high-throughput screening system identifies a small molecule repressive for matrix metalloproteinase-9 expression
    Rajesh R Nair
    Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, USA
    Mol Pharmacol 73:919-29. 2008
  4. pmc ZKSCAN3 is a master transcriptional repressor of autophagy
    Santosh Chauhan
    Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
    Mol Cell 50:16-28. 2013
  5. doi Accelerated urokinase-receptor protein turnover triggered by interference with the addition of the glycolipid anchor
    Hector Avila
    Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
    Biochem J 434:233-42. 2011
  6. pmc Regulation of u-PAR gene expression by H2A.Z is modulated by the MEK-ERK/AP-1 pathway
    Santosh Chauhan
    Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
    Nucleic Acids Res 40:600-13. 2012

Scientific Experts

  • Douglas Boyd
  • Santosh Chauhan
  • Hector Avila
  • Chunhong Yan
  • Rajesh R Nair
  • H Wang
  • Ganiraju Manyam
  • Swati Chauhan
  • Jinesh G Goodwin
  • Ashish M Kamat
  • Jing Wang
  • Sean Hartig
  • Heng Wang
  • Xujun Ma
  • Zhengxin Wang
  • MICHELLE LENNARTZ
  • Bryant G Darnay
  • I Asangani
  • H Allgayer
  • C Yan

Detail Information

Publications6

  1. pmc Histone H3 acetylation and H3 K4 methylation define distinct chromatin regions permissive for transgene expression
    Chunhong Yan
    Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
    Mol Cell Biol 26:6357-71. 2006
    ..We therefore propose a model in which histone H3 acetylation and H3 K4 methylation localized to discrete sites in the mammalian genome mark distinct chromatin functions that dictate transgene expression or silencing...
  2. ncbi Identification of an histone H3 acetylated/K4-methylated-bound intragenic enhancer regulatory for urokinase receptor expression
    H Wang
    Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
    Oncogene 26:2058-70. 2007
    ..Thus, we have defined a novel intragenic enhancer in the u-PAR gene required for constitutive and inducible expression...
  3. ncbi A novel high-throughput screening system identifies a small molecule repressive for matrix metalloproteinase-9 expression
    Rajesh R Nair
    Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, USA
    Mol Pharmacol 73:919-29. 2008
    ....
  4. pmc ZKSCAN3 is a master transcriptional repressor of autophagy
    Santosh Chauhan
    Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
    Mol Cell 50:16-28. 2013
    ..Altogether, our study uncovers an autophagy master switch regulating the expression of a transcriptional network of genes integral to autophagy and lysosome biogenesis/function...
  5. doi Accelerated urokinase-receptor protein turnover triggered by interference with the addition of the glycolipid anchor
    Hector Avila
    Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
    Biochem J 434:233-42. 2011
    ..Thus attenuated u-PAR levels probably reflects accelerated turnover triggered by inefficient addition of the glycolipid moiety...
  6. pmc Regulation of u-PAR gene expression by H2A.Z is modulated by the MEK-ERK/AP-1 pathway
    Santosh Chauhan
    Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
    Nucleic Acids Res 40:600-13. 2012
    ..Z and (ii) MEK-ERK signaling terminating at AP-1 intersects with the epigenetic control of target gene expression by H2A.Z...