SMAR1-derived P44 peptide retains its tumor suppressor function through modulation of p53.
The use of pharmacologically active short peptide sequences is a better option in cancer therapeutics than the full-length protein. Here we report one such 44-mer peptide sequence of SMAR1 (TAT-SMAR1 wild type, P44) that retains the tumor suppressor activity of the full-length protein. The protein transduction domain of human immunodeficiency virus, type 1, Tat protein was used here to deliver the 33-mer peptide of SMAR1 into the cells. P44 peptide could efficiently activate p53 by mediating its phosphorylation at serine 15, resulting in the activation of p21 and in effect regulating cell cycle checkpoint. In vitro phosphorylation assays with point-mutated P44-derived peptides suggested that serine 347 of SMAR1 was indispensable for its activity and represented the substrate motif for the protein kinase C family of proteins. Using xenograft nude mice models, we further demonstrate that P44 was capable of inhibiting tumor growth by preventing cellular proliferation. P44 treatment to tumor-bearing mice prevented the formation of poorly organized tumor vasculature and an increase in hypoxia-inducible factor-1alpha expression, both being signatures of tumor progression. The chimeric TAT-SMAR1-derived peptide, P44, thus has a strong therapeutic potential as an anticancer drug.
Jalota-Badhwar
Archana
A
National Center for Cell Science, Pune University Campus, Ganeshkhind, Pune 411 007.
Kaul-Ghanekar
Ruchika
R
Agharkar Research Institute, G. G. Agarkar Road, Pune 400 004, India.
Mogare
Devraj
D
National Center for Cell Science, Pune University Campus, Ganeshkhind, Pune 411 007.
Boppana
Ramanamurthy
R
National Center for Cell Science, Pune University Campus, Ganeshkhind, Pune 411 007.
Paknikar
Kishore M
KM
Agharkar Research Institute, G. G. Agarkar Road, Pune 400 004, India.
Chattopadhyay
Samit
S
National Center for Cell Science, Pune University Campus, Ganeshkhind, Pune 411 007. Electronic address: samit@nccs.res.in.
D020816:Amino Acid Motifs / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000517:prevention & control*; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C417914:BANP protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53