Rab33A: characterization, expression, and suppression by epigenetic modification.
Rab33A, a member of the small GTPase superfamily, is an X-linked gene that is expressed in brain, lymphocytes, and normal melanocytes, but is downregulated in melanoma cells. We demonstrate that in normal melanocytes Rab33A colocalizes with melanosomal proteins and that a constitutively active GTPase mutant suppresses their transport to the melanosomes. In the brain, Rab33A is present throughout the cortex, as well as in the hippocampal CA fields. A survey of melanocytic lesions demonstrated that aberrant downregulation of Rab33A is an early event that is already prevalent in melanocytes of giant congenital nevi. Analyses of bisulfite-modified DNA revealed that Rab33A is regulated by DNA methylation of a specific promoter region proximal to the transcription initiation site, and that suppression of Rab33A in melanoma cells recapitulates normal processes that control silencing of X-linked genes, but not tissue specific gene expression. This information is important for understanding carcinogenesis as well as other aberrant processes because Rab33A may have an important role in disorders involving X-chromosome-linked genes associated with vesicular transport.
Cheng
Elaine
E
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520-8059, USA.
Trombetta
Sergio E
SE
Kovacs
Daniela
D
Beech
Robert D
RD
Ariyan
Stephan
S
Reyes-Mugica
Miguel
M
McNiff
Jennifer M
JM
Narayan
Deepak
D
Kluger
Harriet M
HM
Picardo
Mauro
M
Halaban
Ruth
R
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D020691:rab GTP-Binding Proteins / Q000032:analysis / Q000235:genetics*
C105244:RAB33A protein, human; C484540:Rab33a protein, mouse; D020691:rab GTP-Binding Proteins