Abstract
The human glioma tumor suppressor candidate region 2 gene product, GLTSCR2, also called ‘protein interacting with carboxyl terminus 1’ (PICT-1), has been implicated in the regulation of two major tumor suppressor proteins, PTEN and p53, and reported to bind the membrane-cytoskeleton regulator of cell signaling, Merlin. PICT-1 is a nucleolar protein, conserved among eukaryotes, and its yeast homolog has been functionally associated with ribosomal RNA processing. By means of confocal microscopy of EGFP and myc-tagged PICT-1 fusion proteins, we delineate that the nucleolar localization of PICT-1 is mediated by two independent nucleolar localization sequences (NoLS). Unlike most NoLSs, these NoLSs are relatively long with flexible boundaries and contain arginine and leucine clusters. In addition, we show that PICT-1 exhibits a nucleolar distribution similar to proteins involved in ribosomal RNA processing, yet does not colocalize precisely with either UBF1 or Fibrillarin under normal or stressed conditions. Identification of the precise location of PICT-1 and the signals that mediate its nucleolar localization is an important step towards advancing our understanding of the demonstrated influence of this protein on cell fate and tumorigenesis.
Highlights
The human glioma tumor suppressor candidate region 2 gene product GLTSCR2, called ‘protein interacting with carboxyl terminus 1’ (PICT-1), was initially identified as a 60 kDa (p60) protein partner of two viral proteins, ICP0 and ICP22, encoded by the herpes simplex virus type 1 [1]
We evidenced that PICT-1 is localized in the nucleolus and predicted the amino acids required for this targeting [19]
Detailed analyses led us to predict that PICT-1 contains six nuclear localization signal (NLS) motifs as well as several short arginine and lysine-rich clusters, the latter sharing similarity with functional nucleolar localization sequences (NoLS) described in nucleolar proteins
Summary
The human glioma tumor suppressor candidate region 2 gene product GLTSCR2, called ‘protein interacting with carboxyl terminus 1’ (PICT-1), was initially identified as a 60 kDa (p60) protein partner of two viral proteins, ICP0 and ICP22, encoded by the herpes simplex virus type 1 [1]. Knockdown of PICT-1 induces anchorage-independent tumor cell growth and decreases susceptibility to apoptotic death stimuli, whereas overexpression of PICT-1 stimulates caspase and mitochondria-independent cell death; both phenomena reported to be PTEN-dependent [4,5,6] Given this involvement of PICT-1 in maintaining PTEN stability, it is expected that loss of function mutations in PICT-1 should result in reduced cellular PTEN levels and concomitant deregulated PI3K-mediated signaling. A recent study challenges the prevailing view of PICT-1, suggesting that PICT-1 is a potentially oncogenic regulator of the MDM2-p53 pathway and acts as a tumor suppressor only under certain conditions, such as loss of p53 function [9] In accord with this alternative understanding of PICT-1 function, low expression of PICT-1 in colorectal and esophageal cancers bearing intact p53 was found to correlate with increased survival [9]
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