ALTERNATIVELY SPLICED FORMS OF CYCLIN D1 MODULATE ENTRY INTO THE CELL-CYCLE IN AN INVERSE MANNER

Alternative splicing of cyclin D1 gene mRNA has recently been demonstr ated, The novel transcript shows no splicing at the downstream exon 3 boundary and encodes a protein with an altered carboxyl-terminal domai n that is a cyclin D1 variant; exon 5 is not included in the coding se quence which terminates downstream of exon 4, We here produced cells t hat exogenously express each form of cyclin D1 and analysed their cell cycle regulation. We found that (1) alternative splicing forms of cyc lin D1 modulated entry into the cell cycle in an inverse manner; (2) b oth splicing forms suppressed cell growth; and (3) cells overexpressin g form [a] were inhibited from entry into and completion of the S phas e, although form [b]-expressing cells shelved no reduction of G1- to S transition. We also found that overexpression of either cyclin D1 for m up-regulated Rb gene products, suggesting that this up-regulation ma y be one of the causes of growth suppression in cyclin D1 overexpressi ng cells.