Phosphorylation of RCC1 on Serine 11 Facilitates G1/S Transition in HPV E7-Expressing Cells

Biomolecules. 2021 Jul 6;11(7):995. doi: 10.3390/biom11070995.

Abstract

Persistent infection of high-risk human papillomavirus (HR-HPV) plays a causal role in cervical cancer. Regulator of chromosome condensation 1 (RCC1) is a critical cell cycle regulator, which undergoes a few post-translational modifications including phosphorylation. Here, we showed that serine 11 (S11) of RCC1 was phosphorylated in HPV E7-expressing cells. However, S11 phosphorylation was not up-regulated by CDK1 in E7-expressing cells; instead, the PI3K/AKT/mTOR pathway promoted S11 phosphorylation. Knockdown of AKT or inhibition of the PI3K/AKT/mTOR pathway down-regulated phosphorylation of RCC1 S11. Furthermore, S11 phosphorylation occurred throughout the cell cycle, and reached its peak during the mitosis phase. Our previous data proved that RCC1 was necessary for the G1/S cell cycle progression, and in the present study we showed that the RCC1 mutant, in which S11 was mutated to alanine (S11A) to mimic non-phosphorylation status, lost the ability to facilitate G1/S transition in E7-expressing cells. Moreover, RCC1 S11 was phosphorylated by the PI3K/AKT/mTOR pathway in HPV-positive cervical cancer SiHa and HeLa cells. We conclude that S11 of RCC1 is phosphorylated by the PI3K/AKT/mTOR pathway and phosphorylation of RCC1 S11 facilitates the abrogation of G1 checkpoint in HPV E7-expressing cells. In short, our study explores a new role of RCC1 S11 phosphorylation in cell cycle regulation.

Keywords: G1/S transition; HPV; RCC1; cervical cancer; phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / metabolism*
  • Cell Line, Transformed
  • G1 Phase*
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Human papillomavirus 16 / metabolism*
  • Humans
  • Keratinocytes / metabolism*
  • Keratinocytes / virology
  • Nuclear Proteins / metabolism*
  • Papillomavirus E7 Proteins / biosynthesis*
  • Phosphorylation
  • S Phase*

Substances

  • Cell Cycle Proteins
  • Guanine Nucleotide Exchange Factors
  • Nuclear Proteins
  • Papillomavirus E7 Proteins
  • RCC1 protein, human
  • oncogene protein E7, Human papillomavirus type 16