Table of Contents

Viewpoints

• • Zhixiang Wang and
  • Michael F. Moran

  Phospholipase C–γ1: A Phospholipase and Guanine Nucleotide Exchange Factor

  Mol Interv October 2002 2:352-355; doi:10.1124/mi.2.6.352
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  Although phospholipase C-γ (PLC-γ) participates in cellular mitogenesis, evidence indicates that the catalytic activity of PLC-γ (to hydrolyze certain phosphoinositides) is nonessential to the process. So how is it that PLC-γ is necessary but its lipase activity is not? Recently published results from Snyder and colleagues describe the ability of PLC-γ to facilitate guanine nucleotide exchange for the recently identified nucleus-localized GTPase PIKE, which acts to enhance the enzymatic activity of phosphatidylinositol 3′-kinase (PI3K). The authors contend that the SH3 domain, rather than the catalytic domain, of PLC-γ is required for aiding PIKE, and furthermore, that the mitogenic activity of PLC-γ depends not on its phospholipase activity, but rather on its interaction with PIKE. Wang and Moran examine the results and piece together a picture of how PLC-γ cooperates with PIKE.

• • Stephen C. Bunnell

  Determining the Destiny of NF-κ B after TCR Ligation: It’s CARMA1

  Mol Interv October 2002 2:356-360; doi:10.1124/mi.2.6.356
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  In T lymphocytes, the “novel” protein kinase C ?? (PKC ??) isoform and the transcription factor nuclear factor-κB (NF-κB) are required for cell proliferation and the production of cytokines in response to T cell activation; however, the molecular interactions that link PKC?? and NF-κB have remained unknown. Two recent reports demonstrate that CARMA1 (caspase recruitment domain-containing membrane-associated guanylate kinase protein-1) bridges the gap between PKC?? and the IκB kinase (IKK)-dependent activation of NF-κB in T cells. Excessive T lymphocyte activation and proliferation are hallmarks of T cell-derived leukemias. Given that CARMA1 is specifically expressed in lymphoid tissues, could pharmacological inhibitors be designed to inhibit CARMA1’s (or PKC??’s) ability to promote the activation of NF-κB?

• • Guojun Cheng,
  • Otabek Imamov,
  • Yoko Omoto,
  • Margaret Warner,
  • and Jan-Åke Gustafsson

  What is the Value of Measuring MTA-1s in Breast Cancer?

  Mol Interv October 2002 2:360-362; doi:10.1124/mi.2.6.360
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  The presence or absence of estrogen receptor (ER) expression in tumor cells affects prognosis and guides treatment choices. Kumar et al. suggest that a shortened form of the metastatic tumor antigen 1 (MTA1s) acts to sequester the estrogen receptor (ER) in the cytoplasm, inhibiting its ability to transactivate specific genes and, presumably, adding to the ER’s ability to transduce non-genomic (cytoplasmic) signaling mechanisms. However, if the cancer is negative for ERα in the nucleus, but is positive for ERα in the cytoplasm, how does this sequestration affect the treatment of the patient or our understanding of the disease process? Cheng et al. caution that these results must be interpreted carefully with regard to what is known about estrogen-dependent and -independent tumor growth and chemotherapeutic strategies to destroy them.